NOVEL PYRAZOLE-BASED HMG CoA REDUCTASE INHIBITORS

ABSTRACT

Novel compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents are described. More specifically, potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG CoA reductase”) are described. Methods of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer&#39;s Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis are also described.

RELATED APPLICATIONS

This application is a continuing application of U.S. application Ser.No. 11/283,264, filed on Nov. 18, 2005, which claims benefit of priorityunder 35 U.S.C 119(e) to U.S. Provisional Application No. 60/630,481filed on Nov. 23, 2004, the contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

High levels of blood cholesterol and blood lipids are conditionsinvolved in the onset of atherosclerosis. The conversion of HMG-CoA tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. It is known that inhibitors of HMG-CoA reductase areeffective in lowering the blood plasma level of low density lipoproteincholesterol (LDL-C), in man. (cf. M. S. Brown and J. L. Goldstein, NewEngland Journal of Medicine, 305, No. 9, 515-517 (1981)). It has beenestablished that lowering LDL-C levels affords protection from coronaryheart disease (cf. Journal of the American Medical Association, 251, No.3, 351-374 (1984)).

To varying degrees, statins interfere with and/or inhibit HMG-CoAreductase from catalyzing the conversion of HMG-CoA to mevalonate. Assuch, statins are collectively potent lipid lowering agents. Thus,statins are the drugs of first choice for management of many lipiddisorders. One representative statin is atorvastatin.

Atorvastatin and pharmaceutically acceptable salts thereof areselective, competitive inhibitors of HMG-CoA reductase. As such,atorvastatin calcium is a potent lipid lowering compound and is thususeful as a hypolipidemic and/or hypocholesterolemic agent, as well asin the treatment of osteoporosis, BPH, diabetes and Alzheimer's disease.A number of patents have issued disclosing atorvastatin including U.S.Pat. Nos. 4,681,893; 5,273,995 and 5,969,156. Other representativestatins include lovastatin, pravastatin, simvastatin and rosuvastatin.

Statin drugs share many features, but also exhibit differences inpharmacologic attributes that may contribute to differences in clinicalutility and effectiveness in modifying lipid risk factors for coronaryheart disease. (Clin. Cardiol. Bol. 26 (Suppl. III), III-32-III-38(2003)). Accordingly, it would be most beneficial to provide a statinhaving a combination of desirable properties including (i) potentreversible inhibition of HMG-CoA reductase, (ii) the ability to producelarge reductions in LDL-C and non-high-density lipoprotein cholesterol(non-HDL-C), (iii) the ability to increase HDL cholesterol (HDL-C), (iv)relative hydrophilicity, (v) tissue selectivity (e.g., selectivity ofeffect or uptake in hepatic cells through selective organic iontransport), (vi) optimal pharmacokinetics or systemic bioavailability soas to minimize any potential risk of systemic adverse effects, while atthe same time having enough systemic availability so that anypleiotropic effects can be observed in the vasculature with statintreatment, (vii) availability of once a day dosing, (viii) a lowpotential for drug-drug interactions, (ix) the ability to lowercirculating very-low-density-lipoprotein (VLDL) as well as the abilityto lower triglyceride levels, (x) prolonged elimination half-life tomaximize effectiveness for lowering LDL-C, (xi) absence or minimalmetabolism via the cytochrome P450 (CYP) enzyme system (e.g., the CYP3A4system) so as to minimize any potential risk of drug-drug interactionswhen statins are given in combination with other drugs, and (xii) reducelevels of C-reactive protein (CRP).

As described below, the present invention relates to compounds andpharmaceutical compositions useful as hypocholesterolemic andhypolipidemic agents. More specifically, the present invention concernscertain potent inhibitors of the enzyme3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG CoA reductase”).The invention further relates to methods of using such compounds andcompositions to treat subjects, including humans, suffering fromhyperlipidemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy(BPH), diabetes and osteoporosis.

SUMMARY OF THE INVENTION

The present invention provides a compound of the formula (I):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein:R₁ is hydrogen, halogen, C₁-C₇alkyl, C₃-C₈cycloalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; more specifically, R₁ is C₁-C₇alkyl orC₃-C₈cycloalkyl; even more specifically, R₁ is isopropyl; where alkyl,cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₁ isoptionally substituted as defined for each of these groups below;R₂ is hydrogen, halogen, C₁-C₇ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, NC—, R_(2b)R_(2a)NCO(CH₂)_(n)—,R_(2b)R_(2a)NS(O)_(n)—, R_(2c)S(O)_(n)—, R_(2b)R_(2a)N(CH₂)_(n)—,R_(2b)-J-C(O)NR_(2a)(CH₂)_(n)—, R_(2b)-J-SO₂NR_(2a)(CH₂)_(n)—,R_(2b)-J-SONR_(2a)(CH₂)_(n), R⁷OOC(CH₂)_(n)—, or R⁷CO(CH₂)_(n)—; morespecifically, R₂ is R_(2b)R_(2a) NCO(CH₂)_(n)—; even more specifically,R₂ is R_(2b)R_(2a)NCO—; where alkyl, cycloalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl of R₂ is optionally substituted as definedfor each of these groups below;J is a direct bond, O, or N;R_(2a) and R_(2b) are each independently hydrogen, C₁-C₁₀ alkyl, C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; morespecifically, R_(2a) and R_(2b) are each independently hydrogen,C₁-C₇alkyl, aryl or aralkyl; even more specifically, R_(2a) and R_(2b)are each independently hydrogen, methyl or benzyl; where alkyl,cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R_(2a) andR_(2b) is optionally substituted as defined for each of these groupsbelow;

or R_(2a) and R_(2b) taken together with the nitrogen to which they areattached form a 4-11 member ring optionally containing at least oneadditional heteroatom selected from O, N and S, said ring beingoptionally substituted with at least one of aryl, aralkyl, heteroaryl,heteroaralkyl, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, halogen, R⁷O—,R⁷OOC(CH₂)_(n)—, R⁷R⁸NCO(CH₂)_(n)—, R⁷O₂S(CH₂)_(n)—, R⁸R⁷NSO₂— or NC—;

R_(2c) is aryl, aralkyl, alkyl, heteroaryl, or heteroaralkyl; wherearyl, aralkyl, alkyl, heteroaryl, or heteroaralkyl of R_(2c) isoptionally substituted as defined for each of these groups below;R⁷ and R⁸ are each independently hydrogen, C₁-C₁₂ alkyl, aryl oraralkyl; where alkyl, aryl or aralkyl of R⁷ and R⁸ is optionallysubstituted as defined for each of these groups below;n is 0, 1 or 2; more specifically, n is 0 or 1; even more specifically,n is 0;R₃ is hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl, aralkyl, heteroaryl,or heteroaralkyl; more specifically, R₃ is aryl; even more specifically,R₃ is phenyl or p-fluorophenyl; where alkyl, cycloalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl of R₃ is optionally substituted as definedfor each of these groups below; and--- is a bond or is absent.

The present invention provides a compound of the following (3R,5R)stereospecific formula (Ia):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R₁, R₂, R₃, and ---- are each as set forthabove.

The invention further provides a compound of formula (II):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R_(2a), R_(2b), n and ---- are each as set forthabove.

The invention further provides a compound of formula (II), as set forthabove, wherein R_(2a) is:

where R₄ and R₅ are each independently hydrogen or lower alkyl;

q is 0, 1 or 2;

each R₆ is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, orcyano; and

p is 0, 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug.

The invention further provides a (3R,5R) stereospecific compound offormula (IIIa):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R_(2a), R_(2b), n and ---- are each as definedabove.

The invention further provides a compound of formula (III):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R_(2a), R_(2b), n and ---- are each as definedabove.

The invention further provides a (3R,5R) stereospecific compound offormula (IIIa):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R_(2a), R_(2b), n and ---- are each as definedabove.

The invention further provides a compound of formula (IV):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R₁, R₂, R₃ and ---- are each as defined above.

The invention further provides a stereospecific compound of formula(IVa):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R₁, R₂, R₃ and ---- are each as defined above.

The invention further provides a compound of formula (V):

or a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the prodrug, wherein R₁, R₂, R₃ and ---- are each as defined above.

The invention further provides a compound of formula (VI):

wherein R₁, R_(2a), R_(2b), and R₃ are each as defined above.

The invention further provides a compound of formula (VII):

wherein R₁, R_(2a), R_(2b), R₃ are each as defined above, and X is asuitable counteranion; more specifically, X is F, Cl, Br, or I anion;even more specifically, X is Br anion.

The invention further provides a compound selected from the groupconsisting of:

-   (3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic    acid;-   7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic    acid;-   7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-heptanoic    acid;-   7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic    acid;-   7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic    acid;-   3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic    acid;-   3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic    acid;-   3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-heptanoic    acid;-   7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic    acid;-   7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic    acid;-   7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic    acid;-   3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   35    (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclobutyl    methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic    acid;-   (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic    acid;-   7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid;-   7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid; and-   (3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic    acid; or

a pharmaceutically acceptable salt, ester, amide or prodrug thereof, ora pharmaceutically acceptable salt of the prodrug.

The invention further provides a compound selected from the groupconsisting of:

-   1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic    acid (3-fluoro-benzyl)-methyl-amide;-   1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic    acid benzyl-methyl-amide; and-   1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic    acid 4-methyl-benzylamide; or

a pharmaceutically acceptable salt, ester, amide or prodrug thereof, ora pharmaceutically acceptable salt of the prodrug.

The invention further provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier,diluent, solvent or vehicle.

The invention further provides a combination of a compound of theinvention and another pharmaceutically active agent, each as describedherein. A pharmaceutical composition comprising the aforementionedcombination and a pharmaceutically acceptable carrier, diluent, solventor vehicle, each as described herein, is also provided by the invention.

The invention further provides a method of preparation of a compound,pharmaceutical composition or combination of the invention, each asdescribed herein.

The invention still further provides a method of treating a subjectsuffering from hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benignprostatic hypertrophy (BPH), diabetes and osteoporosis comprisingadministering a therapeutically effective amount of at least onecompound, pharmaceutical composition or combination of the invention,each as described herein, to the subject in need thereof.

The invention still further provides the use of a compound,pharmaceutical composition, or combination of the invention for treatinga subject suffering from hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benignprostatic hypertrophy (BPH), diabetes and osteoporosis.

The invention still further provides the use of a compound,pharmaceutical composition, or combination of the invention in thepreparation of a medicament for the treatment of a subject sufferingfrom hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy(BPH), diabetes and osteoporosis.

The invention also provides a process comprising the steps of:

(a) reacting a hydroxyl compound VIII:

under conditions sufficient to form a compound IX:

(b) reacting a compound IX under conditions sufficient to form acompound X:

(c) reacting a compound X under conditions sufficient to form a compoundXI:

(d) reacting a compound XI under conditions sufficient to form acompound XII:

(e) reacting a compound XII under conditions sufficient to form acompound XIII:

wherein for steps (a)-(e), R₁, R₃, n, R⁷ are each as defined herein, and

LG-O— together is a leaving group; and

Z is R′″ or R″″CX′=CX″Y where

R′″ is alkenyl;

R″″, X′ and X″ are each hydrogen, alkyl, alkenyl, aryl, heteroaryl, oralkenyl substituent;

Y is either a direct bond or a linker group; and wherein thenon-hydrogen groups of R′″, R″″, X′, X″, or Y are optionally substitutedas defined herein.

The invention further provides a process comprising the steps of:

(a) reacting a compound XIV:

under conditions sufficient to form a compound XV:

(b) reacting a compound XV under conditions sufficient to form acompound XVI:

(c) reacting a compound XVI under conditions sufficient to form acompound XVII:

wherein for steps (a)-(c), R₁, R₃, R_(2a), R_(2b), and n are each asdefined herein and LG-O— together is a leaving group; and

Z is R′″ or R″″CX′=CX″Y where R′″ is alkenyl;

R″″, X′ and X″ are each hydrogen, alkyl, alkenyl, aryl, heteroaryl, oralkenyl substituent;

Y is either a direct bond or a linker group; and wherein thenon-hydrogen groups of R′″, R″″, X′, X″, or Y are optionally substitutedas defined herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless indicated otherwise, the following terms are defined as follows:

The article “a” or “an” as used herein refers to both the singular andplural form of the object to which it refers.

The term “alkyl” as used herein refers to an optionally substituted astraight or branched hydrocarbon of from 1 to 12 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. Thealkyl group may also be optionally substituted with one or more of thesubstituents selected from cycloalkyl, lower alkoxy, lower thioalkoxy,—O(CH₂)₀₋₂CF₃, —O-aryl, aryl, heteroaryl, halogen, haloalkyl, nitro,cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NR′R″,—NR′SO₂R″, —NR′CONR′R″, or —CONR′R″ where R′ and R″ are independently H,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or joined together to form a 4-7 member ring optionallycontaining at least one additional heteroatom selected from N, O and S;or N, R′ and R″ taken together form a 4-7 member ring optionallycontaining at least one additional heteroatom selected from N, O and S.

The term “lower alkyl” as used herein refers to a subset of alkyl whichmeans an optionally substituted straight or branched hydrocarbon radicalhaving from 1 to 7 carbon atoms and includes, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, n-hexyl, n-heptyl and the like. Alternatively, lower alkyl isreferred to as “C₁-C₇ alkyl.” The lower alkyl group may also beoptionally substituted with at least one of the substituents recited forthe term “alkyl”.

The term “alkenyl” as used herein means an optionally substitutedstraight or branched hydrocarbon radical from 2 to 12 carbon atomshaving at least one double bond and includes, for example, ethenyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl,3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl,1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, and the like.The alkenyl group may be optionally substituted with at least one of thesubstituents recited for the term “alkyl”.

The term “alkynyl” as used herein means an optionally substitutedstraight or branched hydrocarbon radical of 2 to 12 carbon atoms havingat least one triple bond and includes, for example, 3-propynyl,1-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, 3-methyl-3-butynyl,1-hexynyl, 3-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-nonynyl,1-decynyl, 1-undecynyl, 1-dodecynyl, and the like. The alkynyl group maybe optionally substituted with at least one of the substituents recitedfor the term “alkyl”.

The term “alkylene” as used herein refers to an optionally substituteddivalent group derived from a straight or branched chain saturatedhydrocarbon having from 1 to 10 carbon atoms by the removal of twohydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene,1,3-propylene, 2,2-dimethylpropylene, and the like. The alkylene groupmay be optionally substituted with one or more of the substituentsselected from lower alkyl, lower alkoxy, lower thioalkoxy,—O(CH₂)₀₋₂CF₃, halogen, haloalkyl, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃,—CO₂H, —CO₂C₁-C₆ alkyl, —NR′R″, or —CONR′R″, where R′ and R″ areindependently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; or N, R′ and R″ taken together form a 4-7member ring optionally containing at least one additional heteroatomselected from N, O and S. Useful alkylene groups have from 1 to 6 carbonatoms (C₁-C₆ alkylene). Examples include, but are not limited to,methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—(CH₂)₃—), and thelike.

The term “halogen” or “halo” as used herein refers to fluorine orfluoro, chlorine or chloro, bromine or bromo and iodine or iodo.

The term “haloalkyl” as used herein refers to an alkyl group where oneor more of the hydrogens has been replaced by a halogen or halo groupeach as defined herein.

The term “heteroatom” as used herein represents oxygen, nitrogen, orsulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO₂) unlessotherwise indicated.

The term “hydrocarbon chain” as used herein refers to an optionallysubstituted straight hydrocarbon of from 2 to 12 carbon atoms. Thehydrocarbon chain is optionally substituted with one or moresubstituents selected from lower alkyl, lower alkoxy, lower thioalkoxy,—O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H,—CO₂C₁-C₆ alkyl, —NR′R″ or —CONR′R″, where R′ and R″ are independentlyH, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; or N, R′ and R″ taken together form a 4-7 member ringoptionally containing at least one additional heteroatom selected fromN, O and S.

The terms “lower alkoxy” and “lower thioalkoxy” as used herein refers to—O-alkyl or —S-alkyl of from 1 to 7 carbon atoms as defined above for“lower alkyl.”

The term “aryl” as used herein refers to a C₅-C₁₄ mono-, bi- orpolycarbocyclic aromatic ring system which is optionally substituted byat least one substituent selected from lower alkyl, lower alkoxy, lowerthioalkoxy, halogen, —O(CH₂)₀₋₂CF₃, —Oaryl, —OSO₂R′, nitro, cyano —OH,—SH, —CF₃, —CO₂H, —CO₂(C₁-C₆)alkyl, —NR′R″, —NR′SO₂R″, —NR′CONR′R″,—SO₁₋₂alkyl, SO₁₋₂aryl, —SO₂NR′R″, or —CONR′R″, where R′ and R″ areindependently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,heteroaryl, heteroaralkyl or joined together to form a 4-7 member ringoptionally containing at least one additional heteroatom selected fromN, O and S; or N, R′ and R″ taken together form a 4-7 member ringoptionally containing at least one additional heteroatom selected fromN, O and S. Examples include, but are not limited to, phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl,3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl,4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl,3,4-dimethylphenyl, and the like.

The term “aralkyl” as used herein means aryl, as defined above, attachedto an alkyl group, as defined above. Linkage to the rest of the moleculemay be through either the aryl or alkyl portion of the aralkyl moiety.The aralkyl group may be optionally substituted by at least one of thesubstituents recited above for “alkyl” and “aryl”. Examples of aralkylinclude, but are not limited to, benzyl, tolyl, and the like.

The term “heteroaryl” as used herein refers to an aryl group, as definedabove, containing one or more heteroatoms, as defined above. Theheteroaryl may be optionally substituted with at least one of thesubstituents recited above for “aryl”. Examples of heteroaryl include,but are not limited to thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl,imidazoyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, isoquinolinyl, quinazolinyl, I-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1-triazolyl,3-triazolyl, 5-triazolyl, I-tetrazolyl, 2-tetrazolyl, 3-tetrazolyl,2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, indolizinyl,isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, quinazolinyl, 1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indolizinyl,2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl,7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 2-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-benzothienyl,3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl,7-benzothienyl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl,6-benzoxazolyl, 7-benzoxazolyl, 1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl,7-quinolinyl, 8-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl,4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl,8-isoquinolinyl, and the like.

The term heteroaralkyl, as used herein refers to heteroaryl, as definedabove, attached to an alkyl group, as defined above. Linkage to the restof the molecule can be either through the heteroaryl or the alkylportion of the heteroaralkyl moiety. The heteroaralkyl may be optionallysubstituted with at least one of those substituents recited above for“alkyl” and “heteroaryl”.

The term “heterocycle” as used herein refers to an optionallysubstituted saturated mono-, bi- or polycyclic ring containing one ormore heteroatoms selected from N, O, and S. The heterocycle may beoptionally substituted with at least one of those substituents recitedabove for “alkylene”. Examples of suitable heterocycles include, but arenot limited to, piperidinyl, pyrrolidinyl, I-piperazinyl, 2-piperazinyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, piperazinyl, azetidinyl,aziridinyl, thietanyl, oxetaryl, and the like.

The term “ring” as used herein includes heteroaryl, heterocycle,cycloalkyl or aryl, each as defined above, and further includes fused,monocyclic, bicyclic, and polycyclic permutations thereof.

The term “cycloalkyl” as used herein refers to an optionally substitutedsaturated cyclic C₃-C₁₂ alkyl group, where alkyl is as defined above.Examples of suitable cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cycloctyl, decalinyl, norpinanyl, or adamantyl. The cycloalkyl ring maybe optionally substituted by with at least one of those substituentsrecited above for “alkyl” or “alkylene”. Examples of substitutedcycloalkyl groups include, but are not limited to, fluorocyclopropyl,2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl,3-phenylcyclopentyl, and the like.

The term “treating” or “treatment” refers to curative, palliative andprophylactic treatment, including reversing, ameliorating, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition.

The term “stereoisomer” as used herein refers to both geometric (e.g.,cis and trans isomers) and/or optical isomers (e.g., R and Senantiomers) of a compound of the invention. Racemic, enantiomeric,diastereomeric and epimeric mixtures of such isomers are contemplated bythe present invention.

When a bond to a substituent is shown to cross the bond(s) connecting 2atoms in a ring, then such substituent may be bonded to any atom in thering, provided the atom will accept the substituent without violatingits valency. When there appears to be several atoms of the substituentthat may bond to the ring atom, then it is the first atom of the listedsubstituent that is attached to the ring, unless indicated otherwise.

When a bond is represented by a line such as “---” this is meant torepresent that the bond may be absent or present provided that theresultant compound is stable and of satisfactory valency. If anasymmetric carbon is created by such a bond, a particularstereochemistry is not to be implied.

Unless indicated otherwise, “compound of the invention” or “compounds ofthe invention” includes the compound itself as well as itspharmaceutically acceptable salt, ester, amide, hydrate, stereoisomer orprodrug thereof, or a pharmaceutically acceptable salt of the prodrug,as well as other embodiments described herein.

As used herein, the following terms have the meanings given: RT or rtmeans room temperature. MP means melting point. MS means massspectroscopy. TLC means thin layer chromatography. [S]at. meanssaturated. [C]one. means concentrated. TBIA means[(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acidtert-butyl ester. DCM means dichloromethane, which is usedinterchangeably with methylene chloride. NBS means N-Bromosuccinimide.“h” means hour. “v/v” means volume ratio or “volume per volume”. “R_(f)”means retention factor. “Tf₂O” or “TfO” means triflic anhydride orC(F)₃S(O)₂OS(O)₂C(F)₃. Ac₂O means acetic anhydride. “[T]rifluorotol.” Or“TFT” means trifluorotoluene. “DMF” means dimethylformamide. “DCE” meansdichloroethane. “Bu” means butyl. “Me” means methyl. “Et” means ethyl.“DBU” means 1,8-Diazabicyclo-[5.4.0]undec-7-ene. “TBS” means “TBDMS” ortert-Butyldimethylsilyl. “DMSO” means dimethyl sulfoxide. “TBAF” meanstetrabutylammonium fluoride. THF means tetrahydrofuran. NBuli or Bulimeans n-butyl lithium. TFA means trifluoroacetic acid. i-Pr meansisopropyl. [M]_(n) means minutes. ml or mL means milliliter. “M” or “m”means molar. “Bn” means benzyl. “PyBOP” meansbromo-tris-pyrrolidino-phosphonium hexafluorophosphate. “OtBu” meanst-butoxy. “Ts” or “Tosyl” means p-toluenesulfonyl. “PS-DIEA” meanspolystyrene-bound diisopropylethylamine. “PS-NCO” meanspolystyrene-bound isocyanate resin. “Ph” means phenyl. As used herein,“hydrogenolysis” means the cleaving of a chemical bond by hydrogen.“EDCI” or “EDC” means 1-(3-dimethylaminopropyl)-3-ethylcarbondiimidehydrochloride. “NMP” means 1-methyl-2-pyrrolidinone.

The term “patient” or “subject” means all mammals including humans.Examples of patients or subjects include humans, cows, dogs, cats,goats, sheep, pigs, and rabbits.

A “therapeutically effective amount” is an amount of a compound of thepresent invention that when administered to a patient treats a symptomof hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy(BPH), diabetes and osteoporosis. As would be understood by one of skillin the art, a “therapeutically effective amount” will vary from subjectto subject and will be determined on a case by case basis. Factors toconsider include, but are not limited to, the subject being treated,weight, health, compound administered, etc.

The term “under conditions sufficient” as used herein refers to thosereaction conditions know in the art that would enable the transformationof one compound to the next.

The term “a pharmaceutically acceptable salt, ester, amide, hydrate,stereoisomer or prodrug” as used herein refers to those acid additionsalts, base addition salts, esters, amides, hydrates, stereoisomers, andprodrugs of the compounds of the present invention which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of patients without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible, of the compounds of the invention.

The term “a pharmaceutically acceptable salt” refers to the relativelynon-toxic, inorganic and organic acid or base addition salts ofcompounds of the invention. These salts can be prepared in situ duringthe final isolation and purification of the compounds or by separatelyreacting the purified compound in its free form with a suitable organicor inorganic acid or base and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, and the like, aswell as non-toxic ammonium, quaternary ammonium, and amine cationsincluding, but not limited to, ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. (See, for example, Berge S. M.,et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19, which isincorporated herein by reference.) The free base form may be regeneratedby contacting the salt form with a base. While the free base may differfrom the salt form in terms of physical properties, such as solubility,the salts are equivalent to their respective free bases for the purposesof the present invention.

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of the invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as aralkyl esters such as, but notlimited to, benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of the invention include amides derived from ammonia, primary(C₁-C₆)alkyl amines and secondary di-(C₁-C₆)alkyl amines wherein thealkyl groups are straight or branched chain. In the case of secondaryamines, the amine may also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C₁-C₃ alkyl primary amines and C₁-C₂ dialkyl secondary amines arepreferred. Amides of the compounds of the invention may be preparedaccording to conventional methods.

“Prodrugs” are intended to include any covalently bonded carrier whichreleases the active parent drug according to Formulae I, Ia, II, IIa,III, IIIa, IV, and V in vivo. Further, the term “prodrug” refers tocompounds that are transformed in vivo to yield the parent compound ofthe above formulae, for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which arehereby incorporated by reference. Examples of prodrugs include, but arenot limited to, acetates, formates, benzoate derivatives of alcohols,and amines present in compounds of the invention.

In some situations, compounds may exist as tautomers. All tautomers of acompound of the invention are encompassed by the present invention.

Certain compounds of the present invention can exist in unsolvated formas well as solvated form including hydrated form. In general, thesolvated form including hydrated form is equivalent to the unsolvatedform and is intended to be encompassed within the scope of the presentinvention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R or S configuration.For example, compounds of formulae (Ia), (IIa), and (IIIa) are shownwith a (3R,5R) configuration. Also envisioned are compounds having a(3S,5S), (3S,5R) or (3R,5S). If a compound of the invention furthercontains another chiral center(s), then that center(s) couldindependently have either an R or S configuration. The present inventionincludes all diastereomeric, enantiomeric, and epimeric forms as well asthe appropriate mixtures thereof. Such stereoisomers may be obtained, ifdesired, by methods known in the art including, for example, theseparation of stereoisomers by chiral chromatographic columns and bychiral synthesis. Additionally, the compounds of the present inventionmay exist as geometric isomers. The present invention includes all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof.

The compounds of the present invention are suitable to be administeredto a patient or subject for the treatment of hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer'sDisease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis.The compounds of the present invention can be administered to apatient/subject alone, or another compound of the invention, or as partof a pharmaceutical composition.

A pharmaceutical composition of the invention contains at least onecompound of the invention and at least one pharmaceutically acceptablecarrier, diluent, solvent or vehicle. The pharmaceutically acceptablecarrier, diluent, solvent or vehicle may be any such carrier known inthe art including those described in, for example, Remington'sPharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit.1985). A pharmaceutical composition of the invention may be prepared byconventional means known in the art including, for example, mixing atleast one compound of the invention with a pharmaceutically acceptablecarrier.

A composition of the invention can be administered to a patient/subjecteither orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracisternally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one (a) inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate; (b) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (c) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (d) humectants, as for example, glycerol; (e)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (f) solution retarders, as for example paraffin; (g)absorption accelerators, as for example, quaternary ammonium compounds;(h) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (i) adsorbents, as for example, kaolin and bentonite; and(j) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include additives,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol, or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 2,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 100 mg per kilogram of bodyweight per day is preferable. The specific dosage used, however, canvary from patient to patient. For example, the dosage can depend on anumbers of factors including the requirements of the patient, theseverity of the condition being treated, and the pharmacologicalactivity of the compound being used. The determination of optimumdosages for a particular patient is well known to those skilled in theart.

The compounds of the invention, as described herein, may be used eitheralone or in combination with another pharmaceutical agent describedherein, in the treatment of the following diseases/conditions:dyslipidemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, peripheral vascular disease, cardiovascular disorders,angina, ischemia, cardiac ischemia, stroke, myocardial infarction,reperfusion injury, angioplastic restenosis, hypertension, diabetes andvascular complications of diabetes, obesity, unstable angina pectoris,Alzheimer's Disease, BPH, osteoporosis, cerebrovascular disease,coronary artery disease, ventricular dysfunction, cardiac arrhythmia,pulmonary vascular disease, renal-vascular disease, renal disease,vascular hemostatic disease, autoimmune disorders, pulmonary disease,sexual dysfunction, cognitive dysfunction, cancer, organ transplantrejection, psoriasis, endometriosis, and macular degeneration. Acombination of the invention may be part of a pharmaceutical compositionfurther containing a pharmaceutically active carrier, diluent, solventor vehicle, each as described herein.

Examples of a suitable pharmaceutically active agent include a CETPinhibitor, a PPAR-activator, an MTP/Apo B secretion inhibitor, acholesterol absorption inhibitor, HDL-cholesterol raising agent,triglyceride lowering agent, a cholesterol synthesis inhibitor, acholesterol modulating agent, a fibrate, niacin, an ion-exchange resin,an antioxidant, an ACAT inhibitor, or bile acid sequestrant; ananti-hypertensive agent; an acetylcholine esterase inhibitor, ananti-diabetic compound, an anti-obesity compound, a thyromimetic agent,an anti-resorptive agent, an anti-osteoporosis agent, anantihypertensive agent, or a drug for the treatment of Alzheimer'sdisease. Specific examples of each of these agents include those knownin the art as well as those specified below.

In combination therapy treatment, both the compounds of the inventionand the other drug therapies are administered to mammals by conventionalmethods. The following discussion more specifically describes thevarious combination aspects of this invention.

Any cholesterol absorption inhibitor known in the art with the abilityof a compound to prevent cholesterol contained within the lumen of theintestine from entering into the intestinal cells and/or passing fromwithin the intestinal cells into the blood stream may be used. Suchcholesterol absorption inhibition activity is readily determinedaccording to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395).Examples include, but are not limited to, ZETIA™ as well as thecholesterol absorption inhibitors described in WO 94/00480.

Any cholesterol ester transfer protein (“CETP”) inhibitor known in theart that inhibits the transfer of cholesteryl ester and triglyceridebetween lipoprotein particles, including high density lipoproteins(HDL), low density lipoproteins (LDL), very low density lipoproteins(VLDL), and chylomicrons may be used. The effect of a CETP inhibitor onlipoprotein profile is believed to be anti-atherogenic. Such inhibitionmay be determined by means known in the art (e.g., Crook et al.Arteriosclerosis 10, 625, 1990; U.S. Pat. No. 6,140,343). Examples ofsuitable CETP inhibitors include, but are not limited to, thosedescribed in U.S. Pat. Nos. 6,197,786, 6,723,752 and 6,723,753.Additional examples of useful CETP inhibitors include the followingcompounds:[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydroxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Torcetrapib™), and3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[3-(1,1,2,2-tetrafluoro-ethoxy)-benzyl]-amino}-1,1,1-trifluoro-propan-2-ol.To address the poor solubility of many of the CETP inhibitors, anappropriate dosage form such as one comprising (1) a solid amorphousdispersion comprising a cholesteryl ester transfer protein (CETP)inhibitor and an acidic concentration-enhancing polymer; and (2) anacid-sensitive HMG-CoA reductase inhibitor, may be necessary. Thisdosage form is more fully described in U.S. Ser. No. 10/739,567.

Any peroxisome proliferator activated receptor (“PPAR”) activator knownin the art that activates or otherwise interacts with a human PPAR maybe used. Three mammalian PPARs have been isolated and termed PPAR-alpha,PPAR-gamma, and PPAR-beta (also known as NUC1 or PPAR-delta). ThesePPARs regulate expression of target genes by binding to DNA sequenceelements, termed PPAR response elements. These elements have beenidentified in the enhancers of a number of genes encoding proteins thatregulate lipid metabolism suggesting that PPARs play a pivotal role inthe adipogenic signaling cascade and lipid homeostasis. PPAR-gammareceptors are associated with regulation of insulin sensitivity andblood glucose levels. PPAR-α activators are associated with loweringplasma triglycerides and LDL cholesterol. PPAR-β activators have beenreported to both increase HDL-C levels and to decrease LDL-C levels.Thus, activation of PPAR-β alone, or in combination with thesimultaneous activation of PPAR-α and/or PPAR-gamma may be desirable informulating a treatment for dyslipidemia in which HDL is increased andLDL lowered. PPAR-activation is readily determined by those skilled inthe art by the standard assays (e.g. US 2003/0225158 and US2004/0157885). Examples of suitable PPAR-activator compounds include,but are not limited to, those described in US 2003/0171377, US2003/0225158, US 2004/0157885, and U.S. Pat. No. 6,710,063. Additionalexamples of useful PPAR-activator compounds include the followingcompounds:[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[4-(4′Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2methyl-phenoxy]-aceticacid;{5-Methoxy-2methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pryidin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid;[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}aceticacid; 3-{5-[2-(-5-Methyl-2phenyl-oxazol-4-yl-ethoxy]-indol-1-yl}-propionic acid;3-{4[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy-1H-indazol-1yl}propanoicacid;2-Methyl-2-{3-[({2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}propionicacid;1-{3′-[2-5-Methyl-2-phenyl-1,3-oxazol-4-y]-1,1′-biphenyl-3-yl}oxy)cyclobutanecarboxylicacid; 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylicacid 3-trifluoromethyl-benzyl ester;2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid;2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid; methyl2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate;2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid;(E)-3-[2-methyl-4-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methoxy)phenyl]-2-propenoicacid;2-{3-chloro-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenyl}aceticacid;2-{2-methyl-4-[({4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid; and pharmaceutically acceptable salts thereof.

Any MTP/Apo B secretion (microsomal triglyceride transfer protein and/orapolipoprotein B secretion) inhibitor known in the art which inhibitsthe secretion of triglycerides, cholesteryl ester and phospholipids maybe used. Such inhibition may be readily determined according to standardassays (e.g., Wetterau, J. R. 1992; Science 258:999). Examples ofsuitable a MTP/Apo B secretion inhibitor include, but are not limitedto, imputapride (Bayer) as well as those described in WO 96/40640 and WO98/23593.

Any ACAT inhibitor known in the art that inhibits the intracellularesterification of dietary cholesterol by the enzyme acyl CoA:cholesterol acyltransferase may be used. Such inhibition may bedetermined readily according to standard assays, such as the method ofHeider et al. described in Journal of Lipid Research. 24:1127 (1983).Examples of suitable ACAT inhibitors include, but are not limited to,those described in U.S. Pat. No. 5,510,379 (carboxysulfonates), WO96/26948 and WO 96/10559 (urea derivatives). Additional examples includeAvasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (Eli Lilly and PierreFabre).

Any lipase inhibitor (e.g., pancreatic lipase inhibitor, a gastriclipase inhibitor) known in the art that inhibits the metabolic cleavageof dietary triglycerides into free fatty acids and monoglycerides may beused. Such lipase inhibition activity may be readily determinedaccording to standard assays (e.g., Methods Enzymol. 286: 190-231).Examples of a suitable lipase inhibitor include, but are not limited to,lipstatin,(2S,3S,5S,7Z,10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoicacid lactone, and tetrahydrolipstatin (orlistat),(2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic1,3 acid lactone, and the variously substituted N-formylleucinederivatives and stereoisomers thereof (U.S. Pat. No. 4,598,089);tetrahydrolipstatin U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and5,643,874; FL-386,1-[4-(2-methylpropyl)cyclohexyl]-2-[-(phenylsulfonyl)oxy]-ethanone, andthe variously substituted sulfonate derivatives related thereto (U.S.Pat. No. 4,452,813); WAY-121898,4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the variouscarbamate esters and pharmaceutically acceptable salts related thereto(U.S. Pat. Nos. 5,512,565; 5,391,571 and 5,602,151); valilactone, and aprocess for the preparation thereof by the microbial cultivation ofActinomycetes strain MG147-CF2 (Kitahara, et al., J. Antibiotics, 40(11), 1647-1650 (1987)); esterastin; ebelactone A and ebelactone B, anda process for the preparation thereof by the microbial cultivation ofActinomycetes strain MG7-G1 (Umezawa, et al., J. Antibiotics, 33,1594-1596 (1980); Japanese Kokai 08-143457, published Jun. 4, 1996). Thecompound tetrahydrolipstatin is especially preferred. Additionalexamples includeN-3-trifluoromethylphenyl-N′-3-chloro-4′-trifluoromethylphenylurea, andthe various urea derivatives related thereto, U.S. Pat. No. 4,405,644;esteracin (U.S. Pat. Nos. 4,189,438 and 4,242,453); andcyclo-O,O′-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and thevarious bis(iminocarbonyl)dioximes related thereto (Petersen et al.,Liebig's Annalen, 562, 205-229 (1949).

Any bile acid sequestrant known in the art may be used. Examples ofsuitable bile acid sequestrants include, but are not limited to,WELCHOL®, COLESTID®, LoCHOLEST®, QUESTRAN® and fibric acid derivatives,such as ATROMID®, LOPID® and TRICOR®.

A compound of the invention can be used in combination with ananti-diabetic compound, i.e. any compound (e.g. insulin) used in thetreating diabetes (especially Type II), insulin resistance, impairedglucose tolerance, or the like, or any of the diabetic complicationssuch as neuropathy, nephropathy, retinopathy or cataracts. Additionalexamples of an anti-diabetic compound include, but are not limited to, aglycogen phosphorylase inhibitor, an aldose reductase inhibitor, asorbitol dehydrogenase inhibitor, a glucosidase inhibitor, and anamylase inhibitor.

Any glycogen phosphorylase inhibitor known in the art that inhibits thebioconversion of glycogen to glucose-1-phosphate which is catalyzed bythe enzyme glycogen phosphorylase may be used. Such glycogenphosphorylase inhibition activity may be readily determined according tostandard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety ofglycogen phosphorylase inhibitors are known to those skilled in the artincluding those described in WO 96/39384 and WO 96/39385.

Any aldose reductase inhibitor known in the art that inhibits thebioconversion of glucose to sorbitol catalyzed by the enzyme aldosereductase. Aldose reductase inhibition may be readily determinedaccording to standard assays (e.g., J. Malone, Diabetes, 29:861-864(1980). “Red Cell Sorbitol, an Indicator of Diabetic Control”).

Any sorbitol dehydrogenase inhibitor known in the art that inhibits thebioconversion of sorbitol to fructose catalyzed by the enzyme sorbitoldehydrogenase may be used. Such sorbitol dehydrogenase inhibitoractivity may be readily determined according to standard assays (e.g.,Analyt. Biochem (2000) 280: 329-331). Examples of a suitable sorbitoldehydrogenase inhibitor include, but are not limited to, those describedin U.S. Pat. Nos. 5,728,704 and 5,866,578.

Any glucosidase inhibitor known in the art that inhibits the enzymatichydrolysis of complex carbohydrates by glycoside hydrolases, for exampleamylase or maltase, into bioavailable simple sugars, for example,glucose. Such glucosidase inhibition activity may be readily determinedby those skilled in the art according to standard assays (e.g.,Biochemistry (1969) 8: 4214).

A generally preferred glucosidase inhibitor includes an amylaseinhibitor. Any amylase inhibitor known in the art that inhibits theenzymatic degradation of starch or glycogen into maltose may be used.Such amylase inhibition activity may be readily determined by thoseskilled in the art according to standard assays (e.g., Methods Enzymol.(1955) 1: 149).

Other preferred glucosidase inhibitors include, but are not limited to,acarbose and the various amino sugar derivatives related thereto (U.S.Pat. Nos. 4,062,950 and 4,174,439); adiposine (U.S. Pat. No. 4,254,256);voglibose,3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol,and the various N-substituted pseudo-aminosugars related thereto (U.S.Pat. No. 4,701,559); miglitol,(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydro-oxymethyl)-3,4,5-piperidinetriol,and the various 3,4,5-trihydroxypiperidines related thereto (U.S. Pat.No. 4,639,436); emiglitate, ethylp-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate,the various derivatives related thereto and pharmaceutically acceptableacid addition salts thereof (U.S. Pat. No. 5,192,772); MDL-25637,2,6-dideoxy-7-O-.beta.-D-glucopyranosyl-2,6-imino-D-glycero-L-gluco-heptitol,the various homodisaccharides related thereto and the pharmaceuticallyacceptable acid addition salts thereof (U.S. Pat. No. 4,634,765);camiglibose, methyl6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-.alpha.-D-glucopyranosidesesquihydrate, the deoxy-nojirimycin derivatives related thereto, thevarious pharmaceutically acceptable salts thereof and synthetic methodsfor the preparation thereof (U.S. Pat. Nos. 5,157,116 and 5,504,078);pradimicin-Q; and salbostatin and the various pseudosaccharides relatedthereto (U.S. Pat. No. 5,091,524).

Any amylase inhibitor known in the art may be used. Examples include,but are not limited to, tendamistat and the various cyclic peptidesrelated thereto (U.S. Pat. No. 4,451,455); AI-3688 and the variouscyclic polypeptides related thereto (U.S. Pat. No. 4,623,714); andtrestatin, consisting of a mixture of trestatin A, trestatin B andtrestatin C and the various trehalose-containing aminosugars relatedthereto, (U.S. Pat. No. 4,273,765).

Additional examples of an anti-diabetic compound for use in acombination of the invention include: biguanides (e.g., metformin),insulin secretagogues (e.g., sulfonylureas and glinides), glitazones,non-glitazone PPAR.gamma. agonists, PPAR.beta. agonists, inhibitors ofDPP-IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists,inhibitors of f-1,6-BPase (Metabasis/Sankyo), GLP-1/analogs (AC 2993,also known as exendin-4), insulin and insulin mimetics (Merck naturalproducts), PKC-beta inhibitors, and AGE breakers.

A compound of the invention can be used in combination with anyanti-obesity agent known in the art. Anti-obesity activity may bereadily determined according to standard assays known in the art.Examples of suitable anti-obesity agents include, but are not limitedto, phenylpropanolamine, ephedrine, pseudoephedrine, phentermine,.beta.sub.3 adrenergic receptor agonists, apolipoprotein-Bsecretion/microsomal triglyceride transfer protein (apo-B/MTP)inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists,monoamine reuptake inhibitors (e.g., sibutramine—U.S. Pat. No.4,929,629), sympathomimetic agents, serotoninergic agents, cannabinoidreceptor antagonists (e.g., rimonabant (SR-141,716A)), dopamine agonists(e.g., bromocriptine—U.S. Pat. Nos. 3,752,814 and 3,752,888),melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin receptor agonists, galanin antagonists, lipaseinhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesinagonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Yantagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones oranalogs thereof, glucocorticoid receptor agonists or antagonists, orexinreceptor antagonists, urocortin binding protein antagonists,glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors(e.g., Axokine™), human agouti-related proteins (AGRP), ghrelin receptorantagonists, histamine 3 receptor antagonists or inverse agonists,neuromedin U receptor agonists, and the like.

Any thyromimetic agent known in the art may also be used in combinationwith a compound of the invention. Thyromimetic activity may be readilydetermined according to standard assays (e.g., Atherosclerosis (1996)126: 53-63). Examples of suitable thyromimetic agents include, but arenot limited to, those described in U.S. Pat. Nos. 4,766,121; 4,826,876;4,910,305; 5,061,798; 5,284,971; 5,401,772; 5,654,468; and 5,569,674.

A compound of the invention may further be used in combination with ananti-resorptive agent (e.g., progestins, polyphosphonates,bisphosphonate(s), estrogen agonists/antagonists, estrogen,estrogen/progestin combinations, Premarin™, estrone, estriol or17.alpha.- or 17.beta.-ethynyl estradiol). Exemplary progestins areavailable from commercial sources and include, but are not limited to:algestone acetophenide, altrenogest, amadinone acetate, anagestoneacetate, chlormadinone acetate, cingestol, clogestone acetate,clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone,dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel,fluorogestone acetate, gestaclone, gestodene, gestonorone caproate,gestrinone, haloprogesterone, hydroxyprogesterone caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenpropionate, progesterone, quingestanolacetate, quingestrone, and tigestol. Preferred progestins aremedroxyprogestrone, norethindrone and norethynodrel.

Exemplary bone resorption inhibiting polyphosphonates includepolyphosphonates of the type described in U.S. Pat. No. 3,683,080.Preferred polyphosphonates are geminal diphosphonates (also referred toas bis-phosphonates), 6-amino-1-hydroxy-hexylidene-bisphosphonic acidand 1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid.Tiludronate disodium, ibandronic acid, alendronate, resindronate, andzoledronic acid are each especially preferred polyphosphonates. Thepolyphosphonates may be administered in the form of the acid, or of asoluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude, but are not limited to, ethane-1-hydroxy 1,1-diphosphonic acid,methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid,methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid, N,N-dimethylamino methane diphosphonicacid, N(2-hydroxyethyl)amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

Any estrogen agonist/antagonist known in the art which bind with theestrogen receptor, inhibit bone turnover and/or prevent bone loss may beused in a combination of the invention. More specifically, an estrogenagonist may be any chemical compound capable of binding to the estrogenreceptor sites in mammalian tissue, and mimicking the actions ofestrogen in one or more tissue. An estrogen antagonist may be anychemical compound capable of binding to the estrogen receptor sites inmammalian tissue, and blocking the actions of estrogen in one or moretissues. Such activities may be readily determined according to standardassays, including estrogen receptor binding assays, and standard bonehistomorphometric and densitometer methods (Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., “The Use of Dual-Energy X-Ray Absorptiometry In Animals”, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice,Martin Dunitz Ltd., London 1994, pages 1-296). Examples of a suitableestrogen agonist/antagonist is3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid (see Willson et al.,Endocrinology, 1997, 138, 3901-3911); tamoxifen (ethanamine,2-(-4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate (1:1)) and related compounds (U.S.Pat. No. 4,536,516); 4-hydroxy tamoxifen (U.S. Pat. No. 4,623,660);raloxifene (methanone,(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)-hydrochloride)(U.S. Pat. No. 4,418,068); toremifene (ethanamine,2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) (U.S. Pat. No. 4,996,225);centchroman (1-(2-((4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-p-pyrrolidine) (U.S.Pat. No. 3,822,287); levormeloxifene; idoxifene((E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone(U.S. Pat. No. 4,839,155);2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol(U.S. Pat. No. 5,488,058);6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol(U.S. Pat. No. 5,484,795);(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanone(WO 95/10513 assigned to Pfizer Inc.); TSE-424 (Wyeth-AyerstLaboratories); arazoxifene; derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide (U.S. Pat. No. 4,133,814);estrogen agonist/antagonists described in U.S. Pat. No. 4,133,814; andestrogen agonist/antagonists described in commonly assigned U.S. Pat.No. 5,552,412.

Especially preferred estrogen agonist/antagonists described in U.S. Pat.No. 5,552,412 are:cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol(also known as lasofoxifene);cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-(6′-pyrrolodinoethoxy-3′-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,-4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-tetrahydro-naphthalene-2-ol;and1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Any anti-osteoporosis agent known in the art may be used in acombination of the invention. Examples include, but are not limited to,parathyroid hormone (PTH) (a bone anabolic agent); parathyroid hormone(PTH) secretagogues (see, e.g., U.S. Pat. No. 6,132,774), particularlycalcium receptor antagonists; calcitonin; and vitamin D and vitamin Danalogs.

Any antihypertensive agent known in the art may be used in a combinationof the invention. Antihypertensive activity may be determined accordingto standard tests (e.g. blood pressure measurements). Examples ofsuitable antihypertensive agents include, but are not limited to, (a)amlodipine and related dihydropyridine compounds (U.S. Pat. Nos.4,572,909 and 5,155,120) such as, but not limited to, amlodipinebenzenesulfonate salt (also termed amlodipine besylate (NORVASC®)) (U.S.Pat. No. 4,879,303) and other pharmaceutically acceptable acid additionsalts of amlodipine (U.S. Pat. No. 5,155,120); (b) calcium channelblockers such as, but not limited to, bepridil (U.S. Pat. No. 3,962,238or U.S. Reissue No. 30,577), clentiazem (U.S. Pat. No. 4,567,175),diltiazem (U.S. Pat. No. 3,562), fendiline (U.S. Pat. No. 3,262,977),gallopamil (U.S. Pat. No. 3,261,859); mibefradil, prenylamine,semotiadil, terodiline, verapamil, aranipine, barnidipine, benidipine,cilnidipine, efonidipine, elgodipine, felodipine, isradipine,lacidipine, lercanidipine, manidipine, nicardipine, nifedipine,nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine,flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, andperhexyline; (c) angiotensin converting enzyme inhibitors(“ACE-inhibitors”) such as, but not limited to, alacepril (U.S. Pat. No.4,248,883), benazepril (U.S. Pat. No. 4,410,520), captopril, ceronapril,delapril, enalapril, fosinopril, imadapril, lisinopril, moveltopril,perindopril, quinapril, ramipril, spirapril, temocapril, andtrandolapril; (d) angiotensin-II receptor antagonists such as, but notlimited to, candesartan (U.S. Pat. No. 5,196,444), eprosartan (U.S. Pat.No. 5,185,351), irbesartan, losartan, and valsartan; (e) beta-adrenergicreceptor blockers (beta- or -blockers) such as, but not limited to,acebutolol (U.S. Pat. No. 3,857,952), alprenolol, amosulalol (U.S. Pat.No. 4,217,305), arotinolol, atenolol, befunolol, betaxolol; and (f)alpha-adrenergic receptor blockers (alpha- or α-blockers) such as, butnot limited to, amosulalol (U.S. Pat. No. 4,217,307), arotinolol (U.S.Pat. No. 3,932,400), dapiprazole, doxazosin, fenspiride, indoramin,labetolol, naftopidil, nicergoline, prazosin, tamsulosin, tolazoline,trimazosin, and yohimbine, which may be isolated from natural sourcesaccording to methods well known to those skilled in the art.

Any compound that is known to be useful in the treatment of Alzheimer'sdisease may be used in a combination of the invention. Such compoundsinclude acetylcholine esterase inhibitors. Examples of knownacetylcholine esterase inhibitors include, but not limited to donepezil(ARICEPT®; U.S. Pat. Nos. 4,895,841, 5,985,864, 6,140,321, 6,245,911 and6,372,760), tacrine (COGNEX®; U.S. Pat. Nos. 4,631,286 and 4,816,456),rivastigmine (EXELON®; U.S. Pat. Nos. 4,948,807 and 5,602,17) andgalantamine (REMINYL; U.S. Pat. Nos. 4,663,318 and 6,099,863).

The present invention contains compounds that can be synthesized in anumber of ways familiar to one skilled in organic synthesis. Thefollowing non-limiting reaction schemes illustrate the preparation ofthe compounds of the present invention. Unless otherwise indicated, allvariables in the reaction schemes and the discussion that follow aredefined above. Also unless indicated otherwise, all starting materialsand/or reagents are commercially available. As would be understood byone of skill in the art, individual compounds may require manipulationof the conditions in order to accommodate various functional groups. Avariety of protecting groups known to one skilled in the art may berequired. Purification, if necessary, may be accomplished on a silicagel column eluted with the appropriate organic solvent system. Also,reverse phase HPLC or recrystallization may be employed.

Scheme 1 describes a general synthetic scheme for the preparation of acompound (12) from an amine (1). As would be understood by one of skillin the art, elimination of the hydrogenation step from the conversion ofcompound (10) to compound (11) provides the corresponding olefinderivative.

Scheme 1a highlights the preparation of compounds of this inventionusing compound (24) as a representative, non-limiting example. As shown,4-fluoroaniline (13) (commercially available from Sigma-Aldrich,Milwaukee, Wis.) was initially converted to a diazonium salt and reactedwith methyl 2-chloroacetoacetate to give hydrazonoyl chloride (14).Treatment of hydrazonoyl chloride (14) with Ag₂CO₃ resulted in in-situgeneration of a nitrilimine that was engaged in a 1,3-dipolarcycloaddition with enone (16) to provide dihydropyrazole (17) as themajor regioisomer. Ceric ammonium nitrate (CAN) oxidation converteddihydropyrazole (17) to pyrazole (18). Through a subsequent series ofroutine manipulations pyrazole (18) was converted to amide (20). Themevalonate side chain was installed by initial reduction of the aldehydefunctionality of intermediate (20) to the corresponding alcohol whichwas converted to phosphonium salt (21) by treatment withtriphenylphosphine hydrobromide. Wittig olefination of phosphonium salt(21) afforded olefin (22). Removal of the acetonide protecting groupwith HCl followed by hydrogenation gave intermediate (23). Eliminationof the hydrogenation step in this last step provides the correspondingolefin derivative. Finally, the ester of compound (23) was hydrolyzed bytreatment with NaOH to give compound (24) which was isolated as acarboxylate salt.

Scheme 1b illustrates another method for the preparation of amide (20).Hydroxy-pyrazole (25) was prepared according to procedures described inattorney docket number PC32787, U.S. Provisional Application No.60/653,469 filed on Feb. 15, 2005 and was then converted to triflate(26). A palladium-mediated coupling of triflate (26) with2-styreneboronic acid afforded compound (27) which was subsequentlysubjected to ozonolysis conditions to provide aldehyde (28). Hydrolysisof the ester of intermediate (28) provided carboxylic acid (29) whichwas finally converted to amide (20) via anN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI)mediated coupling reaction.

Scheme 2 describes an additional method for the preparation of compoundsof this invention. As illustrated, intermediate (10, from Scheme 1) ishydrogenated over Pd—C to provide compound (30). Treatment of compound(30) with 20% TFA/CH₂Cl₂ provides lactone (32) via carboxylic acid (31).Lactone (32) can be utilized as is or converted to the correspondingcarboxylate sodium salt (12) by treatment with NaOH.

Scheme 2a describes an alternative method for the preparation ofcompound (24) utilizing compound (22) as a representative, non-limitingexample of the invention. As illustrated, intermediate (22, from Scheme1a) is hydrogenated over Pd—C to provide compound (33). Treatment ofcompound (28) with 20% TFA/CH₂Cl₂ provides lactone (35) via theintermediacy of carboxylic acid (34). Lactone (35) can be utilized as isor converted to the corresponding carboxylate sodium salt (24) bytreatment with NaOH.

Scheme 3 illustrates a method for preparing compound (12). Aldehyde (8)was prepared as set forth in Scheme 1 and was then condensed with theknown phosphonium ylide (36) [for preparation, see: Konoike, T.; Araki,Y. J. Org. Chem. 1994, 59, 7849-7854] to afford olefin (37). Treatmentof compound (37) with hydrofluoric acid afforded keto-alcohol (38) whichwas subsequently reduced with sodium borohydride to give diol (39). Theolefin of compound (39) was then hydrogenated giving (40) which wastreated with aqueous sodium hydroxide to provide compound (12).

Scheme 3a illustrates a method for preparing compound (46) as arepresentative, non-limiting example of the invention. Aldehyde (41) wasprepared according to the method of Scheme 1 for the preparation ofcompound (8) and was then condensed with the known phosphonium ylide(36) [for preparation, see: Konoike, T.; Araki, Y. J. Org. Chem. 1994,59, 7849-7854] to afford olefin (42). Treatment of compound (42) withhydrofluoric acid afforded keto-alcohol (43) which was subsequentlyreduced with sodium borohydride to give diol (44). The olefin ofcompound (44) was then hydrogenated giving (45) which was treated withaqueous sodium hydroxide to provide compound (46).

Scheme 4 highlights the preparation of compounds of this invention usingcompound (58) as a representative, non-limiting example. As shown, amine(47) is converted to a diazonium salt and reacted with2-chloro-3-oxo-butyronitrile (J. Org. Chem. 1978, 43, 3821-3824) to givehydrazonoyl chloride (48). Treatment of hydrazonoyl chloride (48) withAg₂CO₃ results in in-situ generation of a nitrilimine that is engaged ina 1,3-dipolar cycloaddition with enone (50) to provide dihydropyrazole(51). Ceric ammonium nitrate (CAN) oxidation converts dihydropyrazole(51) to pyrazole (52). Hydrogenation of pyrazole (52) over either Pd—Cor Raney-Ni followed by treatment with R_(2b)C(O)Cl and base providesamide (53). Reduction of (53) followed by oxidation providesintermediate (54). Intermediate (54) can be optionally N-alkylated bytreatment with R_(2a)—Cl and base. The mevalonate side chain isinstalled by initial reduction of the aldehyde functionality ofintermediate (54) to the corresponding to alcohol which is converted tophosphonium salt (55) by treatment with triphenylphosphine hydrobromide.Wittig olefination of phosphonium salt (55) affords olefin (56). Removalof the acetonide protecting group with HCl followed by hydrogenationgives intermediate (57). Elimination of the hydrogenation step in thislast step provides the corresponding olefin derivative. Finally, theester of compound (57) is hydrolyzed by treatment with NaOH to givecompound (58) which is isolated as a carboxylate salt. Notably,substitution of R_(2b)C(O)Cl with R_(2b)SOCl or R_(2b)SO₂Cl in theconversion of (52) to (53) allows for preparation of the correspondingsulfinamide and sulfonamide derivatives of compound (58), respectively.

Scheme 5 highlights the preparation of compounds of this invention usingcompound (72) as a representative, non-limiting example. As shown, amine(59) is converted to a diazonium salt and reacted with methyl2-chloroacetoacetate to give hydrazonoyl chloride (60). Treatment ofhydrazonoyl chloride (60) with Ag₂CO₃ results in in-situ generation of anitrilimine that is engaged in a 1,3-dipolar cycloaddition with enone(62) to provide dihydropyrazole (63). Ceric ammonium nitrate (CAN)oxidation converts dihydropyrazole (63) to pyrazole (64). Hydrogenationof pyrazole (64) over Pd—C followed by reduction and protection providescompound (65). Hydrolysis of (65) gives a carboxylic acid that istreated with diphenylphosphoryl azide in t-BuOH at elevated temperatureto provide compound (66). Acidic deprotection and acylation withR_(2b)C(O)Cl provides intermediate (67) which can be optionallyN-alkylated by treatment with R_(2a)—Cl and base. The mevalonate sidechain is installed by initial deprotection of the alcohol functionalityof intermediate (67) and conversion to phosphonium salt (69) bytreatment with triphenylphosphine hydrobromide. Wittig olefination ofphosphonium salt (69) affords olefin (70). Removal of the acetonideprotecting group with HCl followed by hydrogenation gives intermediate(71). Elimination of the hydrogenation step in this last step providesthe corresponding olefin derivative. Finally, the ester of compound (71)is hydrolyzed by treatment with NaOH to give compound (72) which isisolated as a carboxylate salt. Notably, substitution of R_(2b)C(O)Clwith R_(2b)SOCl or R_(2b)SO₂Cl in the conversion of (66) to (67) allowsfor preparation of the corresponding sulfinamide and sulfonamidederivatives of compound (72). Notably, substitution of R_(2b)C(O)Cl withR_(2b)SOCl or R_(2b)SO₂Cl in the conversion of (66) to (67) allows forpreparation of the corresponding sulfinamide and sulfonamide derivativesof compound (72), respectively.

Scheme 6a illustrates the preparation of compound (78). Hydroxylcompound (73) is reacted under suitable conditions to form compound(74). The “LG-O” of compound (74) together represents any suitableleaving group such as, for example, trifluoromethanesulfonate (CF₃SO₃),mesylate (CH₃SO₃), tosylate (CH₃C₆H₄SO₃), such that upon reaction with asuitable boronic acid or ester affords compound (75). Examples ofsuitable boronic acids and esters include any boronic acid or boronicester that would convert compound (74) to compound (75) including thoseof formula Z-B(OR⁹)(OR¹⁰) where Z is R′″ or R″″CX′=CX″Y where R′″ can bealkenyl; R⁹, R¹⁰, R″″, X′ and X″ can each be hydrogen, alkyl, alkenyl,aryl, heteroaryl, or alkenyl substituent and where R⁹ and R¹⁰ can betaken together with the oxygens to which they are attached to form amono-, bi- or polycyclic ring optionally containing one or more degreesof unsaturation and optionally further substituted; Y is either a directbond or a linker group (e.g. alkylene group); and wherein thenon-hydrogen groups of R⁹, R¹⁰, R′″, R″″, X′, X″, and Y are optionallysubstituted as defined herein.

Compound (75) can then be subjected to ozonolysis conditions to affordaldehyde (76). Hydrolysis of the ester moiety of (76) will providecarboxylic acid (77) which in turn can then be converted to amide (78)via an EDCI mediated coupling reaction. Compound (78) can then beconverted to a compound of the invention in a manner analogous to theconversion of compound (8) to compound (12) illustrated in Scheme 1.

Alternatively, the conversion of compound (74) to compound (75) can beachieved using a compound of formula (R¹⁰O)(R⁹⁰)B-Z-B(OR⁹)(OR¹⁰),wherein Z, R⁹ and R¹⁰ are each independently as defined herein.

Alternatively, the conversion of compound (74) to compound (75) can beachieved using a compound of formula Z-BF₃K, wherein Z is as definedherein.

Scheme 6b illustrates the preparation of compound (82). Hydroxylcompound (79) is reacted under suitable conditions to form compound(80). The “LG-O” of compound (80) together represents any suitableleaving group such as, for example, trifluoromethanesulfonate (CF₃SO₃),mesylate (CH₃SO₃), tosylate (CH₃C₆H₄SO₃), such that upon reaction with asuitable boronic acid or ester affords compound (81). Examples ofsuitable boronic acids and esters include any boronic acid or ester thatwould convert compound (80) to compound (81) including those of formulaZ-B(OR⁹)(OR¹⁰) where Z is R′″ or R″″CX′=CX″Y where R′″ can be alkenyl;R⁹, R¹⁰, R″″, X′ and X″ can each be hydrogen, alkyl, alkenyl, aryl,heteroaryl, or alkenyl substituent and where R⁹ and R¹⁰ can be takentogether with the oxygens to which they are attached to form a mono-,bi- or polycyclic ring optionally containing one or more degrees ofunsaturation and optionally further substituted; Y is either a directbond or a linker group (e.g. alkylene linker group); and wherein thenon-hydrogen groups of R⁹, R¹⁰, R′″, R″″, X′, X″, and Y are optionallysubstituted as defined herein.

Compound (81) can then be subjected to ozonolysis conditions to affordaldehyde (82). Compound (82) can then be converted to a compound of theinvention in a manner analogous to the conversion of compound (8) tocompound (12) illustrated in Scheme 1.

Examples of suitable compounds for the conversion of compound (74) or(80) to, respectively, compound (75) and (81), as illustrated in Schemes6a and 6b, include but are not limited to:

Biological Activity

The compounds of the invention have demonstrated HMG Co-A reductaseinhibition in standard assays commonly employed by those skilled in theart. (See, e.g., J. of Lipid Research 1998; 39:75-84; AnalyticalBiochemistry, 1991; 196:211-214; RR 740-01077 Pharmacology 8 Nov. 82).Accordingly, such compounds as well as their pharmaceutical compositionsand formulations are useful for treating, controlling or preventinginter alia hypercholesterolemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benignprostatic hypertrophy (BPH), diabetes and osteoporosis.

A.) In Vitro Assay

Rat Liver Microsomal Isolation Procedure:

Male Charles River Sprague-Dawley rats were fed with 2.5% cholestyraminein rat chow diets for 5 days before sacrificing. Livers were minced andhomogenized in a sucrose homogenizing solution in an ice bath 10 times.Homogenates were diluted into a final volume of 200 mL, and centrifuged15 min. with a Sorvall Centrifuge at 5° C., 10,000 rpm (12,000×G). Theupper fat layer was removed and the supernatant decanted into freshtubes. This step was repeated one more time before transferring thesupernatant into ultracentrifuge tubes and centrifuged at 36,000 rpm(105,000×G) for an hour at 5° C. The resulting supernatant was discardedand the pellet was added to total of 15 mL 0.2 M KH₂PO₄. Pellets werehomogenized gently by hand about 10 times. Samples were pooled anddiluted into total of 60 mL buffer. The protein concentration of thehomogenate was determined by the Lowry Method using a BCA (Bicinchoninicacid), kit from Pierce Chemical Company. 1 mL aliquots of microsomeswere kept frozen in liquid nitrogen.

HMGCoA (3-Hydroxy-3-methylglutaryl CoA) Reductase Assay:

Materials and Methods:

[3-¹⁴C]-HMGCoA (57.0 mCi/mmol) was purchased from Amersham Biosciences,UK. HMGCoA, mevalonolactone, β-NADPH (β-Nicotinamide AdenineDinucleotide Phosphate, Reduced form) were purchased from Sigma ChemicalCo. AG 1-8× resin was purchased from Bio-Rad Laboratory.

One μL of dimethyl sulfoxide (DMSO) or 1 μL of DMSO containing a testcompound at a concentration sufficient to give a final assayconcentration of between 0.1 nM to 1 mM was placed into each well of aCorning 96 well plate. A Volume of 34 μL of buffer (100 mM NaH₂PO₄, 10mM Imidazole and 10 mM EDTA), (Ethylenediaminetetraacetic acid)containing with 50 μg/mL rat liver microsomes was added into each well.After incubation for 30 min. on ice, 15 μL of ¹⁴C-HMGCoA (0.024 μCi)with 15 mM NADPH, 25 mM DTT, (Dithiothreitol) was added and incubated at37° C. for an additional 45 min. The reaction was terminated by theaddition of 10 μL of HCl followed by 5 μL of mevalonolactone. Plateswere incubated at room temperature overnight to allow lactonization ofmevalonate to mevalonolactone. The incubated samples were applied tocolumns containing 300 μL of AG1-X8 anion exchange resin in a Corningfilter plate. The eluates were collected into Corning 96 well captureplates. Scintillation cocktail (Ultima-Flo-M) was added into each welland plates counted on a Trilux Microbeta Counter. The IC₅₀ values werecalculated with GraphPad software (Prism).

Procedure:

1. Add 1 μL DMSO or compounds into the wells according to the protocol

2. Add 35 μL incubation buffer with the rat microsomes into each well.Incubate 30 min. at 4° C.

3. Add 15 μL ¹⁴C-HMGCoA. Incubate 45 min. at 37° C.

4. Add 10 μL HCl stop reagent

5. Add 5 μL mevelonolactone. Incubate overnight at room temperature

6. Apply the containing into the AG 1-X8 anion exchange resin in Corningfilter plate

7. Collect the eluate into Corning capture plate

8. Add scintillation cocktail Ultima-Flo-M

9. Count on a Trilux Microbeta Counter

10. Calculate IC₅₀ values

Compounds of the invention exhibit a range of IC₅₀ values of less thanabout 500 nM in the aforementioned in vitro assay. Preferably, compoundsof the invention exhibit a range of IC₅₀ values of less than about 100nM. More preferably, compounds of the invention exhibit a range of IC₅₀values of less than about 20 nM.

B.) Cell Assay

Protocol for Sterol Biosynthesis in Rat Hepatocytes:

Cell Culture, Compounds Treatment and Cell Labeling:

Frozen rat hepatocytes purchased from XenoTech (cat# N400572) wereseeded on 6-well collagen I coated plates at a density of 10⁵ cells/perwell. The cells were grown in DMEM, (Dulbecco's Modified Eagle Medium)(Gibco, #11054-020) containing 10% FBS (Fetal Bovine Serum) and 10 mMHEPES, (N-2-hydroxyethyl-piperazine-N′-2-ethane sulfonic acid) (Gibco #15630-080) for 24 hrs. The cells were pre-incubated with compounds for 4hrs and then labeled by incubating in medium containing 1 uCi/per mL of¹⁴C acetic acid for an additional 4 hrs. After labeling, the cells werewashed twice with 5 mM MOPS, (3-[N-morpholino]propane sulfonic acid)solution containing 150 mM NaCl and 1 mM EDTA and collected in the lysisbuffer containing 10% KOH and 80% (vol.) ethanol.

Cholesterol Extraction and Data Analysis:

In order to separate labeled cholesterol from labeled non-cholesterollipids, the cells lysates were subject to saponification at 60° C. for 2hrs. The lysates were then combined with 0.5 volume of H₂O and 2 volumesof hexane, followed by 30 minutes of vigorous shaking. After theseparation of two phases, the upper-phase solution was collected andcombined with 5 volumes of scintillation cocktail. The amount of ¹⁴Ccholesterol was quantified by liquid scintillation counting. The IC₅₀values were calculated with GraphPad software (Prism 3.03).

Compounds of the invention exhibit a range of IC₅₀ values of less thanabout 1000 nM in the aforementioned cell assay. Preferably, compounds ofthe invention exhibit a range of IC₅₀ values of less than about 100 nM.

C.) Protocol for Sterol Biosynthesis in L6 Rat Myoblast:

Cell Culture, Compounds Treatment and Cell Labeling:

L6 rat myoblast purchased from ATCC(CRL-1458) were grown in T-150 ventedculture flasks and seeded on 12-well culture plates at a density of60,000 cells per well. The cells were grown in DMEM, (Dulbecco'sModified Eagle Medium) (Gibco, #10567-014) containing 10% heatinactivated FBS (Fetal Bovine Serum) (Gibco # 10082-139) for 72 hoursuntil reaching confluence. The cells were pre-incubated in media withcompound and 0.2% DMSO (dimethyl sulfoxide) for 3 hours and then labeledby incubating in medium containing compound, 0.2% DMSO and 1 μCi/per mLof ¹⁴C acetic acid for an additional 3 hours. After labeling, the cellswere washed once with 1×PBS (Gibco #14190-144) then lysed overnight at4° C. in buffer containing 10% KOH and 78% (vol.) ethanol.

Cholesterol Extraction and Data Analysis:

Lipid ester bonds were hydrolyzed by saponification of the lysates at60° C. for 2 hours. Sterols (including cholesterol) were extracted fromsaponified lysates by combining with 3 volumes of hexane and mixing bypipette 6 times. The upper organic phase solution was collected andcombined with an equal volume of 1N KOH in 50% methanol and mixed bypipette 6 times. The upper organic phase was collected in ascintillant-coated plate (Wallac #1450-501) and hexanes removed byevaporation at room temperature for 3 hours. The amount of ¹⁴Ccholesterol was quantified by scintillation counting in a Trilux 1450plate reader (Wallac). The IC₅₀ values were calculated from %inhibitions relative to negative controls vs. compound concentration onMicrosoft excel 2000 data analysis wizard using a sigmoid inhibitioncurve model with formula:

y=Bmax(1−(x ^(n)/K^(n) +x ^(n)))+y2

Where K is the IC₅₀ for the inhibition curve, X is inhibitorconcentration, Y is the response being inhibited and Bmax+Y2 is thelimiting response as X approaches zero.

Compounds of the invention have a L6 IC₅₀ value greater than about 100nM in the aforementioned L6 Rat Myoblast. Preferably, compounds of theinvention exhibit a hepatocyte selectivity greater than about ((L6IC₅₀/Rat hepatocyte IC₅₀)>1000), and have a L6 IC₅₀ value greater thanabout 1000 nM.

EXAMPLES Example 1(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

(a) Step A. Preparation of [(4-Fluoro-phenyl)-hydrazono]-chloroaceticacid methyl ester

(Reference: Tetrahedron Asymmetry 1999, 4447-4454): To a solution of4-fluoroaniline (10.0 g, 90.0 mmol; commercially available from SigmaAldrich) in MeOH (80 mL) was added 6 N HCl (80 mL) and the solution wascooled to 0° C. NaNO₂ (12.4 g, 180 mmol) was then slowly added as asolid. The reaction was stirred for 15 min at 0° C. after which timeNaOAc was added as a solid to adjust the reaction to pH 5. Subsequently,a solution of methyl 2-chloroacetoacetate (10.96 mL, 90.0 mmol;commercially available from Sigma Aldrich) in MeOH (40 mL) was slowlyadded at 0° C. The reaction was then allowed to warm to 25° C. andstirred for 12 hr after which time the MeOH was removed under reducedpressure and ether (300 mL) was added. The organic layer was separatedand washed with saturated NaHCO₃ and water prior to drying over Na₂SO₄.The organic layer was concentrated to afford[(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methyl ester (19.42 g,94%) that was utilized without further purification: H-NMR (CDCl₃) δ8.37 (bs, 1H), 7.22-7.12 (m, 2H), 7.00-6.96 (m, 2H), 3.87 (s, 3H).

(b) Step B. Preparation of 4-Methyl-pent-2-enoic acid benzyl ester

To a solution of 4-methyl-2-pentenoic acid (24.0 g, 210 mmol;commercially available from TCI America) in acetone (300 mL) was addedK₂CO₃ (55.8 g, 404 mmol) and the reaction was stirred at 25° C. for 30min. A solution of benzyl bromide (25.2 mL, 212 mmol; commerciallyavailable from Sigma Aldrich) in acetone (100 mL) was then addeddrop-wise. The reaction mixture was subsequently heated to reflux for 16hrs. After cooling to 25° C., the acetone was removed under reducedpressure and ether (300 mL) and water (300 mL) were added and theorganic layer was separated, washed with brine and dried over Na₂SO₄.After concentration, the crude product was subjected to silica gelchromatography (1-5% Ether/Hex) to afford 4-methyl-pent-2-enoic acidbenzyl ester (40.5 g, 98%): H-NMR (CDCl₃) δ 7.36-7.28 (m, 5H), 6.96 (dd,1H), 5.79 (d, 1H), 5.14 (s, 2H), 2.45-2.40 (m, 1H), 1.01 (d, 6H).

(c) Step C. Preparation of1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylicacid 5-benzyl ester 3-methyl ester

To a solution of [(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methylester (20.93 g, 90.8 mmol) and 4-methyl-pent-2-enoic acid benzyl ester(18.54 g, 90.8 mmol) in dioxane (400 mL) at 25° C. was added Ag₂CO₃(63.0 g, 227 mmol; commercially available from Sigma Aldrich). Thereaction was protected from light and stirred at 25° C. for 48 hr.Subsequently, the reaction mixture was filtered through a pad of celiteand the filtrate was concentrated. The crude product mixture wassubjected to silica gel chromatography (5-20% EtOAc/Hex) to afford1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylicacid 5-benzyl ester 3-methyl ester in approximately 90% purity (29.3 g,73%): H-NMR (CDCl₃) δ 7.30-7.24 (m, 3H), 7.15-7.12 (m, 2H), 7.01-6.96(m, 2H), 6.93-6.88 (m, 2H), 5.14 (d, 1H), 5.04 (d, 1H), 4.58 (d, 1H),3.83 (s, 3H), 3.51-3.49 (m, 1H), 2.40-2.36 (m, 1H), 1.00 (d, 3H), 0.69(d, 3H).

(d) Step D. Preparation of1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid5-benzyl ester 3-methyl ester

To a solution of1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylicacid 5-benzyl ester 3-methyl ester (29.3, 73.5 mmol) in THF:Water (1:1,500 mL) at 0° C. was slowly added ceric ammonium nitrate (80.5 g, 147mmol; commercially available from Sigma Aldrich). The reaction wasstirred at 0° C. for 1 hr after which time the THF was removed underreduced pressure and DCM (500 mL) was added. The organic layer wasseparated and washed with water and brine. The organic layer was driedover Na₂SO₄ and concentrated, and the product was purified by silica gelchromatography (5-15% EtOAc/Hex) to provide1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid5-benzyl ester 3-methyl ester (18.95 g, 65%): H-NMR (CDCl₃) δ 7.29-7.21(m, 5H), 7.07 (d, 2H), 6.94 (t, 2H), 5.12 (s, 2H), 3.89 (s, 3H),3.88-3.80 (m, 1H), 1.31 (d, 6H).

(e) Step E. Preparation of1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid3-methyl ester

To a solution of1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid5-benzyl ester 3-methyl ester (18.95 g, 47.8 mmol) in MeOH (300 mL) at25° C. under N₂ was added 10% Pd—C (700 mg; commercially available fromSigma Aldrich). The reaction vessel was evacuated and filled with H₂ andthen stirred at 25° C. for 3 hrs. Subsequently, the reaction vessel wasflushed with N₂ and filtered through a pad of celite. The filtrate wasconcentrated to afford1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid3-methyl ester (14.6 g, 99%) in sufficient purity for use in the nextstep: H-NMR (CDCl₃) δ 7.36-7.31 (m, 2H), 7.11-7.06 (m, 2H), 3.90 (s,3H), 3.86-3.82 (m, 1H), 1.43 (d, 6H).

(f) Step F. Preparation of1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid methyl ester

(Reference: J. Med. Chem. 1996, 549-555) To a solution of1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid3-methyl ester (15.9 g, 51.8 mmol) in THF (300 mL) at 0° C. was slowlyadded BH₃.THF (1.0 M solution in THF, 104 mL, 104 mmol; commerciallyavailable from Sigma Aldrich). The reaction was allowed to warm to 25°C. for 30 min and then heated to 65° C. for 3 hr. After cooling to 25°C., MeOH (50 mL) was slowly added. Subsequently, the solvent was removedunder reduced pressure and a second portion of MeOH (100 mL) was slowlyadded and the solution was stirred at 25° C. for an additional 20 min.The MeOH was then evaporated and EtOAc was added and the organic layerwas washed with 1N NaOH and brine prior to drying over Na₂SO₄. Theorganic layer was concentrated and purified by silica gel chromatography(15-35% EtOAc/Hex) to provide1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid methyl ester (13.6 g, 90%): H-NMR (CDCl₃) δ 7.59-7.56 (m, 2H),7.15-7.11 (m, 2H), 4.57 (s, 2H), 3.89 (s, 3H), 3.66-3.62 (m, 1H), 1.36(d, 6H).

(g) Step G. Preparation of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl ester

To a solution of1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid methyl ester (13.6 g, 46.7 mmol) in CH₂Cl₂ (300 mL) at 25° C. wasadded solid NaHCO₃ (19.6 g, 233 mmol) followed by Dess Martin reagent(20.8 g, 49.0 mmol; commercially available from Lancaster). The reactionwas stirred at 25° C. for 4 hr after which time saturated sodiumbisulfite (50 mL) was added and the organic layer was separated andwashed with water and brine. The organic layer was dried over Na₂SO₄ andconcentrated to an oil that was purified by silica gel chromatography(15% EtOAc/Hex) to afford1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl ester (11.3 g, 84%): H-NMR (CDCl₃) δ 9.95 (s, 1H), 7.42-7.38 (m,2H), 7.17-7.13 (m, 2H), 4.01-3.96 (m, 1H), 3.92 (s, 3H), 1.38 (d, 6H).

(h) Step H. Preparation of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid

To a solution of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl ester (11.34 g, 39.1 mmol) in MeOH (150 mL) was added NaOH (156mL of 1N solution, 156 mmol). The reaction was heated to 60° C. for 4hr. The solvent was then removed under reduced pressure and water (150mL) and Et₂O (100 mL) were added. The organic layer was discarded andthe aqueous layer was acidified with 10% HCl to pH 1 and then extractedwith EtOAc (200 mL×2). The combined organic extracts were dried overNa₂SO₄ and concentrated to give1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid(8.55 g, 79%) as a white solid that required no purification: MS(APCI⁺): m/z 277.0 (M+H).

(i) Step I. Preparation of1-(4-Fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidbenzylamide

To a solution of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid(1.25 g, 4.52 mmol) in CH₂Cl₂ (50 mL) at 25° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g,6.79 mmol; commercially available from Sigma Aldrich) followed by1-hydroxybenzotriazole hydrate (1.04 g, 6.79 mmol; commerciallyavailable from Sigma Aldrich) and the reaction was stirred for 5 min at25° C. Subsequently, benzyl amine (0.533 g, 4.98 mmol; commerciallyavailable from Sigma Aldrich) was added and the reaction was stirred foran additional 4 hrs as a fine white precipitate developed. The organiclayer was washed with 1 N HCl, saturated NaHCO₃ and brine. After dryingand concentration, the product was purified by silica gel chromatography(20% EtOAc/Hex) to provide1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidbenzylamide (0.65 g, 39%): MS (APCI⁺): m/z 366.1 (M+H).

(j) Step J. Preparation of1-(4-Fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid benzylamide

To a solution of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidbenzylamide (0.620 g, 1.70 mmol) in THF:MeOH (40 mL) at 0° C. was addedsodium borohydride (96.3 mg, 2.55 mmol; commercially available fromSigma Aldrich). The reaction was stirred for 30 min at 0° C. at whichpoint TLC analysis indicated the reaction was complete and the solventwas removed under reduced pressure. To the reaction residue was addedethyl acetate (50 mL) and saturated NaHCO₃ (15 mL), and the organiclayer was separated, dried (Na₂SO₄) and concentrated. The resulting oilwas purified by silica gel chromatography (40% EtOAc/Hex) to afford1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid benzylamide (0.540 g, 87%): MS (APCI⁺): m/z 368.1 (M+H).

(k) Step K. Preparation of[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-triphenyl-phosphoniumbromide

To a solution of1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylicacid benzylamide (0.525 g, 1.43 mmol) in acetonitrile (50 mL) was addedtriphenylphosphine hydrobromide (0.49 g, 1.43 mmol; commerciallyavailable from Sigma Aldrich). The reaction was heated to 80° C. for 24hr after which time all starting material was consumed as determined byTLC. The reaction solvent was removed under reduced pressure and theresulting white solid was dried under high vacuum for 12 hr to provide[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-triphenyl-phosphoniumbromide (0.977 g, 98%) in sufficient purity for use in the next step.

(l) Step L. Preparation of(6-{2-[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-vinyl}-2,2-dimethyl-[1R,3R]dioxan-4-yl)-aceticacid tert-butyl ester

To a solution of[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-triphenyl-phosphoniumbromide (0.562 g, 0.811 mmol) in THF:DMSO (50:1, 50 mL) at −78° C. wasadded 1.0 M LiHMDS (Lithium Hexamethyldisilazide; 1.055 mL, 1.055 mmol;commercially available from Sigma Aldrich). An orange color was noted asthe base was added. The reaction mixture was stirred at −78° C. for 5min after which time a solution of(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester(0.252 g, 0.974 mmol; Tetrahedron Lett., 1990, 31, 2545-2548) in THF (10mL) was slowly added. After the addition, the reaction mixture wasstirred at −78° C. for 30 min then allowed to warm to 25° C. and stirredat that temperature for 5 hr. The reaction was quenched by drop-wiseaddition of saturated NH₄Cl. Ethyl acetate (50 mL) was then added andorganic layer was separated, washed with water, dried (Na₂SO₄),concentrated. The crude product was purified by silica gelchromatography (15-20% EtOAc/Hex) to afford(6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-vinyl}-2,2-dimethyl-[1R,3R]dioxan-4-yl)-aceticacid tert-butyl ester (0.24 g, 50%) as an inseparable 1:4 mixture ofcis/trans olefin isomers: MS (APCI⁺): m/z 592.3 (M+H).

(m) Step M. Preparation of(3R,5R)-7-[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid tert-butyl ester

To a solution of(6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester (0.360 g, 0.61 mmol) in MeOH (20 mL) was added 1NHCl (2 mL) and the solution was stirred for 3 hrs at 25° C.Subsequently, the reaction solvent was removed under reduced pressureand ethyl acetate (50 mL) and saturated NaHCO₃ (10 mL) were added. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andconcentrated to afford, after silica gel chromatography (35% EtOAc/Hex),7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester (0.231 g, 69%). Subsequently, to a solution of7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester (0.241 g, 0.437 mmol) in MeOH (20 mL) was added10% Pd—C (50 mg; commercially available from Sigma Aldrich), and thereaction vessel was evacuated and filled with hydrogen gas (via balloon)for 3 hours. The reaction mixture was then filtered through a pad ofcelite and to the filtrate was added The crude product was purified bysilica gel chromatography (30-50% EtOAc/Hex) to provide(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid tert-butyl ester (0.143 g, 59%): MS (APCI⁺): m/z 554.3 (M+H).

(n) Step N. Preparation of(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

To a solution of7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid tert-butyl ester (0.103 g, 0.186 mmol) in MeOH (5 mL) was added 1.0N NaOH (0.190 mL, 0.195 mmol; commercially available from Sigma Aldrich)and the reaction was stirred at 25° C. for 48 hr after which time thereaction was solvent was removed under reduced pressure. The resultingsolid was then azeotroped toluene (3×100 mL) and triturated with diethylether to provide a light yellow solid that was dried under vacuum at 60°C. to afford(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt (0.091 g, 94%): MS (APCI⁺): m/z 498.2 (M+H); H-NMR(DMSO-d₆) δ 8.55 (t, 1H), 7.53-7.49 (m, 2H), 7.33-7.13 (m, 7H), 4.70(bs, 1H), 4.34 (d, 2H), 3.63-3.57 (m, 1H), 3.45-3.42 (m, 1H), 2.74-2.66(m, 1H), 2.58-2.50 (m, 1H), 1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H),1.40-1.10 (m, 10H).

Example 2(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 510.2 (M−H); H-NMR (DMSO-d₆) δ 7.53-7.50 (m,2H), 7.30 (t, 2H), 7.20-7.17 (m, 1H), 7.08-7.05 (m, 3H), 4.33 (s, 3H),3.61-3.59 (m, 1H), 3.45-3.44 (m, 1H), 3.25 (bs, 1H), 2.73-2.67 (m, 1H),2.58-2.51 (m, 1H), 2.24 (s, 3H), 1.94-1.89 (m, 1H), 1.75-1.69 (m, 1H),1.37-1.10 (m, 10H).

Example 3(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 512.2 (M+H); H-NMR (DMSO-d₆) δ 7.53-7.49 (m,2H), 7.30 (t, 2H), 7.14-6.95 (m, 4H), 4.30 (s, 2H), 3.62-3.55 (m, 1H),3.46-3.42 (m, 1H), 3.26-3.19 (m, 1H), 2.69-2.61 (m, 1H), 2.58-2.51 (m,1H), 2.21 (s, 3H), 1.91-1.88 (m, 1H), 1.72-1.66 (m, 1H), 1.34-1.10 (m,10H).

Example 4(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 512.2 (M+H); H-NMR (DMSO-d₆) δ 7.52-7.48 (m,2H), 7.29 (t, 2H), 7.10 (d, 2H), 7.02 (d, 2H), 4.29 (s, 2H), 3.62-3.56(m, 1H), 3.45-3.42 (m, 1H), 3.28 (bs, 1H), 2.73-2.66 (m, 1H), 2.57-2.51(m, 1H), 2.20 (s, 3H), 1.92-1.88 (m, 1H), 1.73-1.67 (m, 1H), 1.53-1.11(m, 10H).

Example 5(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 510.3 (M+H); H-NMR (DMSO-d₆) δ 8.50 (t, 1H),7.53-7.46 (m, 3H), 7.31 (t, 2H), 7.20-7.18 (m, 1H), 7.08-7.06 (m, 3H),6.28 (d, 1H), 5.69 (dd, 1H), 4.35 (d, 2H), 4.19-4.17 (m, 1H), 3.62-3.60(m, 1H), 2.26 (s, 3H), 1.98-1.93 (m, 1H), 1.78-1.72 (m, 1H), 1.44-1.18(m, 8H).

Example 6(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 510.2 (M+H); H-NMR (DMSO-d₆) δ 8.57 (t, 1H),7.54-7.48 (m, 3H), 7.32-7.28 (m, 2H), 7.15-7.13 (m, 2H), 7.06-7.04 (m,2H), 6.27 (d, 1H), 5.68 (dd, 1H), 5.17 (bs, 1H), 4.32 (d, 2H), 4.18-4.17(m, 1H), 3.62-3.58 (m, 1H), 2.21 (s, 3H), 1.96-1.91 (m, 1H), 1.77-1.71(m, 1H), 1.48-1.41 (m, 1H), 1.29-1.23 (m, 7H).

Example 7(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 528.2 (M+H); H-NMR (DMSO-d₆) δ 7.52-7.49 (m,2H), 7.30 (t, 2H), 7.16-7.12 (m, 1H), 6.84-6.81 (m, 2H), 6.72-6.70 (m,1H), 4.31 (s, 2H), 3.66 (s, 3H), 3.62-3.57 (m, 1H), 3.47-3.43 (m, 1H),3.29-3.18 (m, 2H), 2.70-2.66 (m, 1H), 2.56-2.54 (m, 1H), 1.92-1.88 (m,1H), 1.72-1.67 (m, 1H), 1.36-1.10 (m, 10H).

Example 8(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1. MS (APCI⁺): m/z 528.2 (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.32-7.28 (m, 2H), 7.21-7.16 (m, 3H), 6.80 (d, 2H), 4.27 (s, 2H),3.65 (s, 3H), 3.64-3.49 (m, 3H), 2.73-2.69 (m, 1H), 2.57-2.49 (m, 1H),1.96-1.92 (m, 1H), 1.77-1.71 (m, 1H), 1.37-1.10 (m, 10H).

Example 9(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 526.3 (M+H); H-NMR (DMSO-d₆) δ 8.63 (t, 1H),7.52-7.49 (m, 2H), 7.34-7.28 (m, 3H), 7.19-7.10 (m, 2H), 6.83-6.82 (m,2H), 6.73 (d, 1H), 6.28 (dd, 1H), 5.73-5.69 (m, 1), 5.15-5.14 (m, 1H),4.34 (d, 2H), 4.19-4.15 (m, 1H), 3.66 (s, 3H), 3.62-3.61 (m, 1H),1.99-1.94 (m, 1H), 1.78-1.74 (m, 1H), 1.49-1.42 (m, 1H), 1.25-1.19 (m,7H).

Example 10(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 524.1 (M+H); H-NMR (DMSO-d₆) δ 8.55 (t, 1H),7.52-7.48 (m, 2H), 7.37 (s, 1H), 7.30 (t, 2H), 7.18 (d, 2H), 6.80 (d,1H), 5.68 (dd, 1H), 5.15 (bs, 1H), 4.29 (d, 2H), 4.17-4.15 (m, 1H), 3.66(s, 3H), 3.62-3.58 (m, 1H), 1.98-1.93 (m, 1H), 1.79-1.73 (m, 1H),1.49-1.42 (m, 1H), 1.30-1.23 (m, 7H).

Example 11(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1 MS (APCI⁺): m/z 512.1 (M−H); H-NMR (DMSO-d₆) δ 7.42-7.06 (m,9H), 4.61 (s, 1H), 4.49 (s, 1H), 3.87-3.71 (m, 4H), 3.47-3.42 (m, 1H),2.80-2.69 (m, 3H), 1.97-1.94 (m, 1H), 1.79-1.75 (m, 1H), 1.57-1.21 (m,10H).

Example 12(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 530.3 (M−H); H-NMR (DMSO-d₆) δ 7.48-7.01 (m,8H), 4.63 (s, 1H), 4.52 (s, 1H), 3.62-3.58 (m, 1H), 3.46-3.44 (m, 1H),2.89-2.85 (m, 1H), 2.83 (s, 3H), 2.74-2.66 (m, 1H), 2.54-2.45 (m, 1H),1.93-1.88 (m, 1H), 1.73-1.67 (m, 1H), 1.53-1.10 (m, 10H).

Example 13(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 530.2 (M−H); H-NMR (DMSO-d₆) δ 7.52-7.08 (m,8H), 4.71 (bs, 1H), 4.60 (s, 1H), 4.48 (s, 1H), 3.60-3.58 (m, 1H),3.47-3.42 (m, 1H), 2.89-2.84 (m, 1H), 2.80 (s, 3H), 2.73-2.70 (m, 1H),2.67-2.58 (m, 1H), 1.92-1.88 (m, 1H), 1.72-1.66 (m, 1H), 1.36-1.26 (m,3H), 1.16-1.11 (m, 7H).

Example 14(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 526.22 (M+H).

Example 15(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 512.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.27 (d, 1H),7.54-7.50 (m, 2H), 7.46-7.07 (m, 8H), 5.11-5.03 (m, 1H), 4.70 (d, 1H),3.65-3.52 (m, 1H), 3.49-3.38 (m, 1H), 3.22-3.12 (m, 1H), 2.73-2.65 (m,1H), 2.57-2.49 (m, 1H), 1.94-1.89 (m, 1H), 1.74-1.68 (m, 1H), 1.40-1.06(m, 13H).

Example 16(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 512.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.27 (d, 1H),7.54-7.50 (m, 2H), 7.44 (s, 1H), 7.34-7.07 (m, 7H), 5.11-5.03 (m, 1H),4.70 (d, 1H), 3.65-3.52 (m, 1H), 3.49-3.38 (m, 1H), 3.22-3.12 (m, 1H),2.73-2.65 (m, 1H), 2.57-2.49 (m, 1H), 1.94-1.89 (m, 1H), 1.74-1.68 (m,1H), 1.40-1.06 (m, 13H).

Example 17(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: H-NMR (DMSO-d₆) δ 7.50-7.17 (m, 9H), 6.24 (d, 1H), 5.82 (dd,1H), 4.53 (s, 1H), 4.19-4.18 (m, 1H), 3.63-3.59 (m, 1H), 2.97-2.94 (m,1H), 2.83 (d, 2H), 1.96-1.92 (m, 1H), 1.78-1.72 (m, 1H), 1.47-1.43 (m,1H), 1.35-1.29 (m, 1H), 1.19-1.10 (m, 6H).

Example 18(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) m/z 510.3 (M+H); H-NMR (DMSO-d₆) δ 8.38 (d, 1H),7.53-7.50 (m, 2H), 7.35-7.09 (m, 8H), 6.27 (d, 1H), 5.69 (dd, 1H), 5.15(s, 1H), 5.09 (t, 1H), 4.18-4.17 (m, 1H), 3.63-3.57 (m, 1H), 3.24-3.17(m, 1H), 1.96 (dd, 1H), 1.77 (dd, 1H), 1.54-1.18 (m, 13H).

Example 19(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 510.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.38 (d, 1H),7.54-7.50 (m, 2H), 7.35-7.09 (m, 8H), 6.28 (d, 1H), 5.69 (dd, 1H),5.21-5.07 (m, 2H), 4.17 (q, 1H), 3.63-3.57 (m, 1H), 3.24-3.17 (m, 1H),1.96 (dd, 1H), 1.77 (dd, 1H), 1.54-1.18 (m, 13H).

Example 20(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 512.6 m/z (M+H); H-NMR (DMSO-d₆) δ 8.19-7.95 (m,1H), 7.55-7.01 (m, 10H), 4.78-4.63 (m, 1H), 3.66-3.51 (m, 1H), 3.42-3.35(m, 1H), 3.26-3.08 (m, 1H), 2.78-2.60 (m, 2H), 2.58-2.40 (m, 2H),1.98-1.83 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.05 (m, 13H).

Example 21(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺): m/z 422.2 (M+H); H-NMR (DMSO-d₆) δ 7.96-7.95 (m,1H), 7.64 (s, 1H), 7.51-7.47 (m, 2H), 7.34-7.28 (m, 2H), 4.72 (bs, 1H),3.59-3.51 (m, 1H), 3.47-3.42 (m, 1H), 2.72-2.43 (m, 5H), 1.91-1.86 (m,1H), 1.70-1.64 (m, 1H), 1.47-1.11 (m, 10H).

Example 22(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 436.6 m/z (M+H); H-NMR (DMSO-d₆) δ 8.09-7.97 (m,1H), 7.55-7.45 (m, 2H), 7.35-7.03 (m, 4H), 4.78-4.63 (m, 1H), 3.66-3.55(m, 1H), 3.51-3.39 (m, 1H), 3.26-3.08 (m, 3H), 2.78-2.60 (m, 1H),2.58-2.40 (m, 1H), 1.98-1.83 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.05 (m,13H).

Example 23(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 436.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.55-7.45 (m,2H), 7.35-7.03 (m, 4H), 4.78-4.55 (m, 1H), 3.66-3.55 (m, 1H), 3.51-3.39(m, 1H), 2.98-2.77 (d, 6H), 2.78-2.60 (m, 1H), 2.58-2.40 (m, 1H),1.98-1.83 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.05 (m, 10H).

Examples 24-29

Examples 24-29 can be prepared in a manner analogous to the method ofScheme 2:

Ex Compound R₆ ^(′) R₆ ^(″) R₆ ^(′″) 247-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H- H H Hpyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid 253R,5R-Dihydroxy-7-[4-isopropyl-5-(2-methyl- Me H Hbenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic acid 263R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl- H Me Hbenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic acid 273R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl- H H Mebenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic acid 283R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy- H OMe Hbenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic acid 293R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy- H H OMebenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic acid

Examples 30-32

Examples 30-32 can be prepared in a manner analogous to the method ofScheme 2

Ex. Compound R₆ ^(′) R₆ ^(″) 307-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H- H Hpyrazol-3-yl]-3R,5R-dihydroxy-heptanoic acid 317-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro- F Hphenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid 327-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro- H Fphenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid

Examples 33-35

Examples 33-35 can be prepared in a manner analogous to the method ofScheme 2

Ex Example R_(2b) R₄ R₅ 333R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)- H Me Hα-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid 343R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)- H H Meα-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid 353R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α-methyl- Me Me Hbenzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}- heptanoic acid

Examples 36-39

Examples 36-39 can be prepared in a manner analogous to the method ofScheme 2

Ex Compound R₆ ^(′) R₆ ^(″) R₆ ^(′″) 363R,5R-Dihydroxy-7-{4-isopropyl-5-(2-methyl- Me H Hbenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic acid37 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl- H H Mebenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic acid38 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy- H OMe Hbenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic acid39 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy- H H OMebenzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic acid

Examples 40-42

Examples 40-42 can be prepared in a manner analogous to the method ofScheme 2

Ex. Compound R_(2a) R_(2b) 403R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro- Me Hphenyl)-2H-pyrazol-3-yl)-heptanoic acid 417-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3- EthylH yl)-3R,5R-dihydroxy-heptanoic acid 427-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol- Me Me3-yl)-3R,5R-dihydroxy-heptanoic acid

Examples 43-45

Examples 43-45 can be prepared in a manner analogous to the method ofScheme 2

Ex Compound R_(2b) R₄ R₅ 437-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro- Me H Hphenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid 443R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)- H Me Hα-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]hept-6-enoic acid 453R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)- H H Meα-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid

Example 46(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.51-7.40, 7.35-7.22, 7.20-7.06, 5.70, 4.71, 4.57,4.44, 3.65-3.55, 3.47-3.41, 3.11, 2.93-2.83, 2.78, 2.77, 2.68-2.63,2.60-2.48, 2.46-2.44, 1.93-1.86, 1.75-1.64, 1.42-1.23, 1.05-1.10.

Example 47(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 484.2 m/z (M+H); H-NMR (DMSO-d₆) δ 9.93 (s, 1H),7.75-7.50 (m, 4H), 7.45-7.23 (m, 5H), 7.05 (t, 1H), 5.72 (s, 1H),3.68-3.54 (m, 1H), 3.51-3.41 (m, 1H), 3.25-3.18 (m, 1H), 2.80-2.67 (m,1H), 2.63-2.51 (m, 1H), 1.97-1.84 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.13(m, 10H).

Example 48(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 516.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.53-7.50 (m,2H), 7.33-7.26 (m, 3H), 7.09-6.96 (m, 3H), 4.35 (s, 2H), 3.60-3.58 (m,1H), 3.46-3.43 (m, 1H), 2.70-2.65 (m, 1H), 2.55-2.45 (m, 1H), 1.94 (dd,1H), 1.74-1.68 (m, 1H), 1.37-1.10 (m, 10H).

Example 49(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 516.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.52-7.48 (m,2H), 7.32-7.26 (m, 4H), 7.08-7.04 (m, 2H), 4.31 (s, 2H), 3.61-3.55 (m,1H), 3.45-3.42 (m, 1H), 2.73-2.66 (m, 1H), 2.57-2.53 (m, 1H), 1.91-1.87(m, 1H), 1.71-1.65 (m, 1H), 1.35-1.05 (m, 10H).

Example 50(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.55-7.51 (m,2H), 7.35-7.10 (m, 7H), 3.61-3.58 (m, 1H), 3.45-3.43 (m, 1H), 3.10 (bs,1H), 2.57-2.50 (m, 1H), 2.49-2.44 (m, 1H), 1.92-1.87 (m, 1H), 1.72-1.66(m, 1H), 1.58 (s, 6H), 1.34-1.08 (m, 10H).

Example 51(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.52-7.49 (m,2H), 7.32-7.28 (t, 2H), 7.23-7.17 (m, 4H), 4.33 (s, 2H), 4.31 (s, 2H),3.59-3.57 (m, 1H), 3.45-3.43 (m, 1H), 3.20 (s, 3H), 2.57-2.49 (m, 1H),2.48-2.42 (m, 1H), 1.92-1.87 (m, 1H), 1.71-1.66 (m, 1H), 1.29-1.09 (m,10H).

Example 52(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.53-7.40, 7.38-7.24, 7.23-7.03, 6.90-6.80, 4.75,4.54, 4.41, 3.69, 3.67, 3.63-3.53, 3.49-3.40, 2.94-2.81, 2.78, 2.76,2.74-2.63, 2.61-2.48, 2.24, 1.94-1.83, 1.72-1.66, 1.53, 1.42-1.20,1.18-1.05.

Example 53(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.48-7.40, 7.31-7.21, 7.19-7.00, 5.70, 4.71, 4.58,4.47, 3.65-3.55, 3.47-3.41, 3.11, 2.93-2.83, 2.78, 2.77, 2.68-2.63,2.60-2.48, 2.46-2.44, 1.93-1.86, 1.75-1.64, 1.42-1.23, 1.05-1.10.

Example 54(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.48-7.44, 7.40-7.11, 6.88-6.76, 4.71, 4.59, 4.50,3.68, 3.59, 3.45, 2.89-2.86, 2.81, 2.80, 2.76-2.63, 2.58-2.52,1.94-1.89, 1.74-1.68, 1.42-1.23, 1.17-1.12.

Example 55(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.48-7.44, 7.39-7.32, 7.31-7.08, 4.71, 4.62, 4.47,3.64-3.53, 3.51-3.39, 3.24-3.18, 2.95-2.80, 2.78-2.63, 2.62-2.49,1.93-1.89, 1.73-1.67, 1.41-1.23, 1.22-1.08, 1.07-1.02.

Example 56(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 540.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.49-7.41, 7.38-7.07, 4.71, 4.57, 4.44, 4.38-4.24,4.09-4.03, 3.64-3.50, 3.47-3.28, 2.95-2.80, 2.77-2.63, 2.61-2.45, 2.24,1.94-1.90, 1.74-1.65, 1.43-1.02.

Example 57(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1S-phenyl-ethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.46-7.42, 7.35-7.12, 5.94-5.91, 5.25-5.21,3.60-3.52, 3.46-3.41, 2.92-2.83, 2.71-2.65, 2.60, 2.54, 1.92-1.88,1.72-1.66, 1.49-1.11.

Example 58(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 504.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.33-7.28 (m, 2H), 3.60-3.56 (m, 1H), 3.44-3.40 (m, 1H), 3.29-3.15(m, 3H), 2.98 (d, 2H), 2.68-2.61 (m, 1H), 2.52-2.46 (m, 1H), 1.92-1.87(m, 1H), 1.72-1.66 (m, 2H), 1.62-1.11 (m, 18H)-.

Example 59(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1S-p-tolyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 526.1 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.32-7.27 (m, 2H), 7.22-7.17 (m, 2H), 7.03-7.01 (m, 2H), 5.03-5.01(m, 1H), 3.60-3.56 (m, 1H), 3.46-3.41 (m, 1H), 2.68-2.46 (m, 1H),2.56-2.52 (m, 1H), 2.19 (s, 3H), 1.92-1.87 (m, 1H), 1.72-1.67 (m, 1H),1.37-1.08 (m, 13H).

Example 60(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.2 m/z (M+H); H-NMR (DMSO-d₆) δ 8.56 (t, 1H),7.55-7.52 (m, 2H), 7.35-7.11 (m, 6H), 4.73 (bs, 1H), 4.37-4.33 (m, 4H),3.64-3.62 (m, 1H), 3.48-3.46 (m, 1H), 3.23 (s, 3H), 2.72-2.69 (m, 1H),2.59-2.45 (m, 1H), 1.95 (dd, 1H), 1.78-1.73 (m, 1H), 1.40-1.13 (m, 10H).

Example 61(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[1S-(3-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.26 (bs, 1H),7.53-7.50 (m, 2H), 7.33-7.29 (m, 2H), 7.17-7.10 (m, 1H), 6.91-6.88 (m,2H), 6.73-6.70 (m, 1H), 5.05-5.01 (m, 1H), 3.66 (s, 3H), 3.61-3.57 (m,1H), 3.45-3.41 (m, 1H), 2.71-2.65 (m, 1H), 2.57-2.50 (m, 1H), 1.93-1.88(m, 1H), 1.73-1.67 (m, 1H), 1.37-1.11 (m, 13H).

Example 62(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[1S-(4-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 542.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.35-8.08 (m,1H), 7.65-7.40 (m, 2H), 7.38-7.15 (m, 4H), 6.93-6.70 (m, 2H), 5.17-4.95(m, 1H), 4.80-4.60 (m, 1H), 3.80-3.50 (s, 3H), 2.80-2.58 (m, 1H),2.56-2.50 (m, 1H), 2.40-2.18 (m, 1H), 1.98-1.82 (m, 1H), 1.79-1.63 (m,1H), 1.54-0.78 (m, 14H).

Example 63(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 580.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.66-7.23, 4.71, 4.61, 3.58, 3.44, 3.27, 3.26,2.61-2.44, 1.91-1.86, 1.71-1.65, 1.29-1.05.

Example 64(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 580.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.70-7.64, 7.5-7.44, 7.36-7.12, 4.71, 4.61,3.59-3.56, 3.45-3.41, 2.86, 2.85, 2.73-2.43, 1.91-1.87, 1.71-1.66,1.36-1.09.

Example 65(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 450.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.33-7.28 (m, 2H), 3.60-3.57 (m, 1H), 3.46-3.41 (m, 1H), 3.09 (t,2H), 2.68-2.64 (m, 1H), 2.57-2.50 (m, 1H), 1.93-1.88 (m, 1H), 1.73-1.67(m, 1H), 1.43-1.10 (m, 12H), 0.79 (t, 3H).

Example 66(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 567.2 m/z (M−H); H-NMR (DMSO-d₆) δ 8.64-8.59 (m,1H), 7.67-7.35 (m, 4H), 7.30-7.05 (m, 4H), 4.72 (s, 1H), 4.36 (d, 2H),3.65-3.35 (m, 2H), 2.90 (s, 3H), 2.82 (s, 3H), 1.91-1.83 (m, 1H),1.75-1.62 (m, 1H), 1.40-1.05 (m, 13H).

Example 67(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 499.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.62-8.51 (m,1H), 8.45-8.37 (m, 1H), 7.70 (t, 1H), 7.62-7.40 (m, 2H), 7.39-7.12 (m,4H), 4.73 (s, 1H), 4.45 (d, 2H), 3.63-3.55 (m, 1H), 3.48-3.39 (m, 1H),2.80-2.62 (m, 1H), 2.60-2.43 (m, 1H), 1.92-1.88 (m, 1H), 1.72-1.63 (m,1H), 1.50-1.02 (m, 12H).

Example 68(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1R-phenyl-ethylcarbamoyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 528.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.26 (d, 1H),7.54 (t, 1H), 7.50-7.16 (m, 9H), 5.12-5.00 (m, 1H), 4.97-4.92 (m, 1H),4.71 (m, 1H), 3.70-3.50 (m, 2H), 3.48-3.38 (m, 1H), 3.22-3.05 (m, 1H),2.78-2.60 (m, 1H), 2.58-2.48 (m, 1H), 1.91-1.86 (m, 1H), 1.73-1.67 (m,1H), 1.40-1.00 (m, 13H).

Example 69(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 478.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.59-7.38, 7.36-7.11, 4.78-4.64, 3.64-3.44,3.42-3.30, 2.98-2.80, 2.78-2.63, 2.60-2.38, 1.93-1.87, 1.72-1.66,1.40-1.10.

Example 70(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 450.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.65 (d, 1H),7.52-7.45 (m, 2H), 7.35-7.23 (m, 1H), 4.70 (s 1H), 4.03-4.93 (m, 1H),3.64-3.56 (m, 1H), 3.42-3.38 (m, 1H), 3.22-3.15 (m, 1H), 2.73-2.60 (m,1H), 2.57-2.43 (m, 1H), 1.94-1.89 (m, 1H), 1.74-1.65 (m, 1H), 1.40-1.17(m, 9H), 1.15-1.03 (m, 9H).

Example 71(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 518.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.46-7.39, 7.32-7.26, 3.61-3.57, 3.44-3.41,3.16-3.12, 2.85, 2.83, 2.68-2.60, 2.58-2.51, 1.92-1.87, 1.72-1.45,1.39-1.23, 1.15-1.03, 0.94-0.91, 0.76-0.71.

Example 72(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 490.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.32-7.28 (m, 2H), 3.58-3.56 (m, 1H), 3.48-3.43 (m, 1H), 3.10 (d,2H), 2.68-2.61 (m, 1H), 2.56-2.50 (m, 1H), 2.08-2.03 (m, 1H), 1.90-1.85(m, 1H), 1.69-1.64 (m, 1H), 1.66-1.09 (m, 18H).

Example 73(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 464.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.95 (bs, 1H),7.51-7.48 (m, 2H), 7.32-7.28 (m, 2H), 3.60-3.56 (m, 1H), 3.45-3.43 (m,1H), 3.18-3.13 (m, 1H), 2.96 (d, 2H), 2.71-2.65 (m, 1H), 2.56-2.52 (m,1H), 1.92-1.87 (m, 1H), 1.88-1.74 (m, 2H), 1.39-1.05 (m, 10H), 0.79 (d,6H).

Example 74(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 487.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.47 (m,2H), 7.32-7.28 (m, 2H), 3.59-3.56 (m, 1H), 3.44-3.24 (m, 1H), 3.18-3.12(m, 2H), 2.67-2.61 (m, 1H), 2.46-2.43 (m, 1H), 1.90-1.86 (m, 1H),1.68-1.46 (m, 1H), 1.55-1.51 (m, 1H), 1.39-1.05 (m, 12H), 0.82 (d, 6H).

Example 75(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 476.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.75 (d, 1H),7.51-7.47 (m, 2H), 7.33-7.28 (m, 2H), 4.70 (d, 1H), 4.14-4.09 (m, 1H),3.59-3.51 (m, 1H), 3.46-3.41 (m, 1H), 3.18-3.13 (m, 1H), 2.71-2.66 (m,1H), 2.56-2.50 (m, 1H), 1.92-1.88 (m, 1H), 1.81-1.70 (m, 3H), 1.61-1.52(m, 2H), 1.43-1.39 (m, 2H), 1.38-1.15 (m, 10H).

Example 76(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 538.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofdiastereomers] δ 7.51-7.47, 7.33-7.06, 6.93-6.92, 5.37-5.32, 5.14-5.11,3.79-3.28, 2.96-2.89, 2.78-2.19, 1.92-1.56, 1.24-0.87.

Example 77(3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 476.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.47 (m,2H), 7.32-7.27 (m, 2H), 3.61-3.57 (m, 1H), 3.44-3.41 (m, 1H), 3.20-3.16(m, 1H), 2.67-2.63 (m, 1H), 2.54-2.51 (m, 1H), 1.92-1.84 (m, 3H),1.78-1.57 (m, 5H), 1.41-1.06 (m, 1.06).

Example 78(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 548.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.48-7.01, 4.71-4.69, 3.59-3.57, 3.44, 2.88,2.84-2.81, 2.72-2.68, 2.56-2.61, 1.92-1.88, 1.72-1.69, 1.40-1.24,1.14-1.08.

Example 79 (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 462.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.48 (m,2H), 7.32-7.28 (m, 2H), 3.61-3.59 (m, 1H), 3.43-3.41 (m, 1H), 3.18-3.17(m, 1H), 3.01 (d, 2H), 2.68-2.64 (m, 1H), 2.56-2.49 (m, 1H), 1.93-1.88(m, 1H), 1.73-1.67 (m, 1H), 1.39-1.01 (m, 10H), 0.33-0.29 (m, 2H),0.16-0.12 (m, 2H).

Example 80(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 548.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.53-7.00, 4.71, 4.64, 4.60, 3.61-3.57, 3.44-3.42,2.84, 2.81, 2.72-2.66, 2.56-2.53, 1.92-1.87, 1.72-1.66, 1.36-1.09.

Example 81(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: H-NMR [Mixture of rotamers at 25° C.] (DMSO-d₆) δ 7.51-7.25,4.72, 4.67, 4.57, 3.66-3.61, 3.51-3.42, 2.90, 2.87, 2.76-2.71,2.52-2.44, 1.96-1.91, 1.76-1.72, 1.39-1.08.

Example 82(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 464.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.97 (t, 3H),7.56-7.51 (m, 3H), 7.35-7.31 (m, 2H), 4.74-4.73 (m, 1H), 3.69-3.59 (m,1H), 3.56-3.40 (m, 1H), 3.21-3.12 (m, 3H), 2.78-2.63 (m, 1H), 2.60-2.43(m, 1H), 1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.47-1.33 (m, 2H),1.31-1.21 (m, 12H), 1.20-1.10 (m, 1H), 0.85 (t, 3H).

Example 83(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 476.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.66-7.60, 7.50-7.41, 7.34-7.27, 4.75-4.68,3.63-3.60, 3.59-3.55, 3.52-3.43, 2.95-2.82, 2.80-2.63, 2.61-2.45,1.95-1.90, 1.74-1.68, 1.60-1.51, 1.46-1.43, 1.42-1.38, 1.36-1.25,1.24-1.13.

Example 84(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) H-NMR (DMSO-d₆) [Mixture of rotamers at 25° C.] δ7.66-7.25, 4.73, 4.69, 4.59, 3.66-3.59, 3.52-3.43, 2.87, 2.86,2.76-2.71, 2.58-2.52, 1.94-1.89, 1.74-1.68, 1.34-1.08.

Example 85(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 490.1 m/z (M+H); H-NMR (DMSO-d₆) δ 7.82-7.76 (m,1H), 7.59-7.43 (m, 2H), 7.39-7.25 (m, 2H), 4.78-4.64 (m, 1H), 3.80-3.58(m, 2H), 3.56-3.40 (m, 1H), 3.23-3.08 (m, 1H), 2.78-2.60 (m, 1H),2.59-2.43 (m, 1H), 1.96-1.86 (m, 1H), 1.80-1.62 (m, 4H), 1.60-1.43 (m,1H), 1.41-1.04 (m, 18H).

Example 86(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 523.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.78-8.75 (m,1H), 7.78-7.74 (m, 2H), 7.61-7.51 (m, 2H), 7.49-7.40 (m, 2H), 7.39-7.29(m, 2H), 4.76-4.71 (m, 1H), 4.43-4.38 (m, 2H), 3.68-3.58 (m, 1H),3.57-3.42 (m, 1H), 3.23-3.16 (m, 2H), 2.80-2.62 (m, 1H), 2.61-2.50 (m,1H), 1.95-1.91 (m, 1H), 1.75-1.68 (m, 1H), 1.43-1.08 (m, 12H).

Example 87(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 523.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.78-8.75 (m,1H), 7.77-7.60 (m, 2H), 7.59-7.40 (m, 4H), 7.38-7.23 (m, 2H), 4.76-4.72(m, 1H), 4.43-4.38 (m, 2H), 3.68-3.58 (m, 1H), 3.57-3.42 (m, 1H),3.23-3.16 (m, 2H), 2.80-2.62 (m, 1H), 2.61-2.50 (m, 1H), 1.95-1.91 (m,1H), 1.75-1.68 (m, 1H), 1.43-1.08 (m, 12H).

Example 88(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 504 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.49-7.31, 3.65-3.61, 3.49-3.46, 3.36, 3.23, 2.89,2.87, 2.74-2.72, 2.68-2.46, 2.28-2.21, 1.95-1.91, 1.76-1.16.

Example 89(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

Step A. Preparation of Methyl-(2-methyl-benzyl)-amine

To a solution of 2-methylbenzaldehyde (10.0 g, 83.23 mmol) in MeOH at25° C. was added methylamine (40% in H₂O, 25.85 g, 332.9 mmol). Thereaction mixture was stirred at 25° C. for 30 min after which time itwas cooled to 0° C. and NaBH₄ (6.30 g, 166.5 mmol) was addedportion-wise. The reaction mixture was then warmed to 25° C. and stirredfor an additional 1 hr. The solvent was removed under reduced pressureand water and CH₂Cl₂ were added. The organic layer was separated andwashed with saturated NaHCO₃ and brine. After drying over Na₂SO₄,organic phase was concentrated to afford desiredmethyl-(2-methyl-benzyl)-amine (10.49 g, 93.2%) as an oil of sufficientpurity for use in the next reaction: MS (APCI⁺) 136.3 m/z (M+H); H-NMR(CDCl₃) δ 7.35-7.08 (m, 3H), 3.73 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H).

Step B. Preparation of1-(4-Fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl-(2-methyl-benzyl)-amide

To a solution of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid(1.50 g, 5.43 mmol) in CH₂Cl₂ (100 mL) at 25° C. was added EDCI (1.56 g,8.14 mmol) followed by HOBt.H₂O (1.25 g, 8.14 mmol) and the reaction wasstirred for 10 min at 25° C. Subsequently,methyl-(2-methyl-benzyl)-amine (1.10 g, 8.14 mmol) was added and thereaction was stirred for an additional 6 hrs at 25° C. The organic layerwas then washed with HCl, saturated NaHCO₃ and brine. After drying overNa₂SO₄ and concentration, the product was purified by columnchromatography (10-25% EtOAc/Hex) to afford desired1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl-(2-methyl-benzyl)-amide as an oil (1.53 g, 71.6%). MS (APCI⁺)394.2 m/z (M+H).

Step C. Preparation of5-(tert-Butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoicacid methyl ester

To a solution of1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acidmethyl-(2-methyl-benzyl)-amide (1.53 g, 3.89 mmol) in toluene (80 mL)was added3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-15-phosphanylidene)-hexanoicacid methyl ester [prepared according to the published method: Konoike,T.; Araki, Y. J. Org. Chem. 1994, 59, 7849-7854] (2.70 g, 5.06 mmol) andthe reaction was heated to 95° C. for 16 hrs. After cooling to 25° C.,the solvent was removed under reduced pressure and product was runthrough pad of silica gel (20-30% EtOAc/Hex) to afford5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoicacid methyl ester (2.48 g, 98.1%): MS (APCI⁺) 650.4 m/z (M+H).

Step D. Preparation of7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-Pyrazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid methyl ester

To a solution of5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoicacid methyl ester (2.48 g, 3.82 mmol) in MeCN (40 mL) at 25° C. wasadded HF (2.5 mL of 48% in water). Reaction was stirred at 25° C. for 16hrs. Subsequently, EtOAc (100 mL) and water (100 mL) were added and theorganic layer was separated, dried and concentrated. Product waspurified by column chromatography (30%-50% EtOAc-Hex) to afford7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoicacid methyl ester (2.03 g, 98.0%): MS (APCI⁺) 536.4 m/z (M+H).

Step E.7-{2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid methyl ester

To a solution of7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoicacid methyl ester (2.04 g, 3.81 mmol) in THF (100 mL) and MeOH (30 mL)at −78° C. was added diethylmethoxyborane (4.95 mL of 1.0 M solution,4.95 mmol). Reaction was stirred at −78° C. for 1 hrs after which timeNaBH₄ (166 mg, 4.38 mmol) was added. Reaction mixture was stirred at−78° C. for 2 hr and then warmed to 0° C. after which time glacialacetic acid (0.5 mL) was added. Reaction was diluted with EtOAc andwater and organic layer was separated and washed with sat. NaHCO₃ andbrine prior to concentration. The resulting crude oil was then dissolvedin MeOH (50 mL) and evaporated again. Subsequently a second amount ofMeOH (50 mL) was added and the solution was stirred at 25° C. for 12 hrsafter which time it was concentrated and purified by columnchromatography (40-60% EtOAc/Hex) to afford7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid methyl ester (1.66 g, 81.1%): MS (APCI⁺) 538.4 m/z (M+H).

Step F.7-{2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid methyl ester

To a solution of7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid methyl ester (1.190 g, 2.21 mmol) in MeOH (50 ml) was added Pd—C(0.1 g). The reaction vessel was evacuated, flushed with nitrogen andthen filled with hydrogen (via balloon). Reaction was stirred at 25° C.for 4 hrs. Reaction was then flushed with nitrogen and filtered througha pad of celite. The filtrate was concentrated and purified by columnchromatography (30-40% EtOAc/Hex) to afford7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid methyl ester (0.792 g, 66%): MS (APCI⁺) 540.2 m/z (M+H).

Step G.(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

To a solution of7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid methyl ester (0.7920 g, 1.47 mmol) in MeOH (5 ml), NaOH solution(1.028N, 1.50 ml, 1.54 mmol) was added. The reaction mixture was stirredat 25° C. for 12 hrs. After solvent was evaporated, the crude productwas dried azeotropically with toluene (×3). It was dissolved inMeOH/CH₂Cl₂ mixture (1:9, 10 ml) and diluted with CH₂Cl₂ (15 ml). It wasfiltered through cotton and the filtrate was concentrated, trituratedwith Et₂O for 12 hrs. The product was isolated by filtration and driedunder vacuum at 60° C. for 12 hrs to afford(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt (798 mg, 99%): MS (APCI⁺) 526.3 m/z (M+H); H-NMR(DMSO-d₆) [Mixture of rotamers at 25° C.] δ 7.79-7.65, 7.58-7.46,7.41-7.24, 7.22-7.07, 4.85-4.60, 3.62-3.58, 3.46-3.44, 2.89-2.85, 2.84,2.74-2.66, 2.54-2.45, 2.29, 1.93-1.88, 1.73-1.67, 1.53-1.10.

Example 90(3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 530.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.55-7.10, 4.74, 4.70, 4.67, 3.67-3.62, 3.51-3.44,2.92, 2.88, 2.75-2.69, 2.59-2.53, 1.95-1.90, 1.75-1.69, 1.39-1.11.

Example 91(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 548.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.21, 4.62, 4.50, 3.56-3.61, 3.51-3.45, 2.86,2.84, 2.76-2.69, 2.54-2.50, 1.94-1.90, 1.75-1.71, 1.41-1.07.

Example 92(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 556.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.55-7.51 (m,2H), 7.34-7.30 (m, 2H), 7.25-7.10 (m, 4H), 4.37 (s, 2H), 4.36 (s, 2H),3.66-3.61 (m, 1H), 3.49-3.43 (m, 1H), 3.41 (q, 2H), 2.76-2.71 (m, 1H),2.57-2.51 (m, 1H), 1.97-1.92 (m, 1H), 1.77-1.71 (m, 1H), 1.39-1.12 (m,10H), 1.09 (t, 3H).

Example 93(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: H-NMR (DMSO-d₆) δ 7.55-7.51 (m, 2H), 7.35-7.30 (m, 2H),7.23-7.10 (m, 4H), 4.32 (s, 2H), 3.65-3.60 (m, 1H), 3.49-3.44 (m, 1H),3.23-3.21 (m, 1H), 2.75-2.71 (m, 1H), 2.69-2.61 (m, 1H), 2.51 (q, 2H),1.97-1.92 (m, 1H), 1.77-1.71 (m, 1H), 1.39-1.14 (m, 10H), 1.11 (t, 3H).

Example 94(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 567.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.86 (s, 1H),8.78 (t, 1H), 8.15 (d, 1H), 7.58-7.54 (m, 2H), 7.48 (d, 1H), 7.37-7.33(m, 2H), 4.80-4.73 (m, 1H), 4.55 (d, 2H), 3.70-3.58 (m, 1H), 3.55-3.42(m, 1H), 3.24-3.20 (m, 1H), 2.80-2.63 (m, 1H), 2.61-2.42 (m, 1H),1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.42-1.30 (m, 1H), 1.29-1.20 (m,10H), 1.17-1.12 (m, 1H).

Example 95(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 567.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.85 (t, 1H),8.70 (s, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 7.58-7.56 (m, 2H), 7.39-7.34(m, 2H), 4.73-4.78 (m, 1H), 4.51 (d, 2H), 3.67-3.55 (m, 1H), 3.45-3.45(m, 1H), 3.26-3.18 (m, 1H), 2.80-2.68 (m, 1H), 2.64-2.55 (m, 1H),1.97-1.92 (m, 1H), 1.77-1.65 (m, 1H), 1.42-1.21 (m, 10H), 1.20-1.10 (m,2H).

Example 96(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 573.3 m/z (M+H); H-NMR (DMSO-d₆) [A mixture ofdiastereomers] δ 8.11-8.08, 7.54-7.40, 7.36-7.28, 4.76-4.63, 3.64-3.58,3.51-3.40, 3.22-3.11, 3.03-2.96, 2.80-2.60, 2.59-2.47, 2.40-2.35,1.95-1.90, 1.82-1.62, 1.60-1.40, 1.39-1.02.

Example 97(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 540.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.50 (t, 1H),7.54-7.50 (m, 3H), 7.49-7.34 (m, 2H), 7.32-7.11 (m, 3H), 4.76-4.70 (m,1H), 4.31 (d, 1H), 3.68-3.59 (m, 1H), 3.50-3.41 (m, 1H), 3.36-3.29 (m,1H), 3.24-3.16 (m, 1H), 2.84-2.76 (m, 1H), 2.75-2.63 (m, 1H), 2.60-2.43(m, 1H), 1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.42-1.30 (m, 1H),1.29-1.16 (m, 10H), 1.13 (d, 6H).

Example 98(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3R-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 552.1 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.52-7.43. 7.42-7.38, 7.36-7.03, 4.80-4.63,4.60-4.50, 3.80-3.53, 3.50-3.33, 3.26-3.24, 3.20-3.02, 2.98-2.78,2.76-2.44, 1.98-1.87, 1.84-1.61, 1.59-1.15.

Example 99(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3S-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: H-NMR (DMSO-d₆) [Mixture of rotamers at 25° C.] δ 7.54-7.09,4.74-4.72, 4.62-4.51, 3.78-3.57, 3.51-3.45, 3.08-3.02, 2.89-2.80,2.79-2.49, 1.97-1.85, 1.83-1.61, 1.58-1.11.

Example 100(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺). 513.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.64 (t, 1H),8.34 (d, 1H), 7.59-7.51 (m, 3H), 7.49-7.38 (m, 1H), 7.35-7.31 (m, 2H),7.15 (d, 1H), 4.77-4.68 (m, 1H), 4.32 (d, 2H), 3.63-3.59 (m, 1H),3.49-3.40 (m, 1H), 3.24-3.19 (m, 1H), 2.76-2.62 (m, 1H), 2.60-2.44 (m,1H), 2.38 (s, 3H), 1.95-1.91 (m, 1H), 1.75-1.70 (m, 1H), 1.40-1.19 (m,10H), 1.19-1.11 (m, 1H).

Example 101(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 434.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.09-8.04 (m,1H), 7.50-7.46 (m, 2H), 7.32-7.27 (m, 2H), 7.22-7.12 (m, 1H), 6.26 (d,1H), 5.66 (dd, 1H), 5.13 (s, 1H), 4.21-4.14 (m, 1H), 3.65-3.55 (m, 1H),3.41-3.27 (m, 1H), 3.23-3.15 (m, 2H), 2.00-1.94 (m, 1H), 1.80-1.75 (m,1H), 1.49-1.40 (m, 1H), 1.38-1.07 (m, 8H), 1.02 (t, 3H).

Example 102(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 482.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.82-7.58 (m,5H), 7.43-7.23 (m, 4H), 7.02 (t, 1H), 6.17 (d, 1H), 5.76 (t, 1H),4.95-4.71 (m, 1H), 3.97-3.81 (m, 1H), 3.58-3.41 (m, 1H), 3.21-3.05 (m,1H), 2.55-2.39 (m, 1H), 1.84-1.71 (m, 1H), 1.62 (m, 1H), 1.40-1.08 (m,8H), 0.83-0.65 (m, 1H).

Example 103(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 502.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.51-7.47 (m,2H), 7.33-7.28 (m, 2H), 6.26 (d, 1H), 5.68 (dd, 1H), 4.19-4.16 (m, 1H),3.61-3.59 (m, 1H), 3.42-3.39 (m, 1H), 3.00 (d, 2H), 1.97-1.92 (m, 2H),1.78-1.72 (m, 1H), 1.63-0.88 (m, 19H).

Example 104(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 448.3 m/z (M+H).

Example 105(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 448.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.83-7.77 (m,1H), 7.60-7.41 (m, 2H), 7.40-7.22, (m, 2H), 6.27 (d, 1H), 5.71-5.14 (m,1H), 5.22-5.04 (m, 1H), 4.26-4.10 (m, 1H), 4.08-4.00 (m, 1H), 3.67-3.51(m, 1H), 2.01-1.89 (m, 1H), 1.82-1.70 (m, 1H), 1.50-1.40 (m, 1H),1.37-1.05 (m, 15H).

Example 106(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 462.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.05 (bs, 1H),7.51-7.48 (m, 2H), 7.32-7.28 (m, 2H), 6.26 (d, 1H), 5.69 (dd, 1H),4.19-4.16 (m, 1H), 3.62-3.58 (m, 1H), 3.18 (d, 2H), 1.96-1.92 (m, 1H),1.79-1.72 (m, 2H), 1.48-1.41 (m, 1H), 1.29-1.23 (m 7H), 0.80 (d, 6H).

Example 107(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 474.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.52-7.47 (m,2H), 7.31-7.27 (m, 2H), 6.26 (d, 1H), 5.68 (dd, 1H), 4.16-4.10 (m, 2H),3.63-3.60 (m, 1H), 3.21-3.15 (m, 1H), 1.97-1.93 (m, 1H), 1.79-1.73 (m,4H), 1.60-1.53 (m, 2H), 1.47-1.40 (m, 4H), 1.36-1.17 (m, 7H).

Example 108(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: (M+H); H-NMR (DMSO-d₆) δ 8.01 (bs, 1H), 7.50-7.47 (m, 2H),7.32-7.28 (m, 2H), 6.26 (d, 1H), 5.67 (dd, 1H), 4.17-4.16 (m, 1H),3.16-3.59 (m, 1H), 3.19-3.17 (m, 2H), 1.97-1.92 (m, 1H), 1.78-1.72 (m,1H), 1.56-1.49 (m, 3H), 1.39-1.19 (m, 8H), 0.82 (d, 6H).

Example 109 (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 460.3 m/z (M+H); H-NMR (DMSO-d₆) δ 7.50-7.46 (m,2H), 7.31-7.27 (m, 2H), 6.26 (d, 1H), 5.56 (dd, 1H), 4.19-4.16 (m, 1H),3.63-3.59 (m, 1H), 3.30-3.26 (m, 1H), 3.04 (d, 2H), 1.95-1.90 (m, 1H),1.77-1.71 (m, 1H), 1.39-1.10 (m, 8H), 0.98-0.94 (m, 1H), 0.34-0.31 (m,2H), 0.17-0.14 (m, 2H).

Example 110(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 462.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.10-8.05 (m,1H), 7.52-7.47 (m, 2H), 7.35-7.28 (m, 2H), 7.01 (s, 1H), 6.31-6.27 (m,1H), 6.73-5.67 (m, 1H), 5.16 (s, 1H), 4.23-4.16 (m, 1H), 3.65-3.58 (m,1H), 3.36-3.18 (m, 3H), 2.03-1.95 (m, 1H), 1.85-1.79 (m, 1H), 1.53-1.33(m, 3H), 1.31-1.21 (m, 10H), 0.85 (t, 3H).

Example 111(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 594.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.52-7.46, 7.36-7.25, 6.29-6.24, 5.86-5.73, 5.17,4.71, 4.61, 4.24-4.21, 3.68-3.65, 2.91, 2.88, 1.99-1.95, 1.83-1.79,1.49-1.12.

Example 112(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 488.2 m/z (M+H); H-NMR (DMSO-d₆) δ 7.82-7.76 (m,1H), 7.58-7.43 (m, 1H), 7.41 (s, 1H), 7.35-7.27 (m, 2H), 6.29 (d, 1H),5.71 (dd, 1H), 5.21-5.18 (m, 1H), 4.21-4.18 (m, 1H), 3.78-3.66 (m, 1H),3.65-3.60 (m, 1H), 3.22-3.17 (m, 1H), 2.00-1.96 (m, 1H), 1.82-1.60 (m,4H), 1.39-1.40 (m, 2H), 1.38-1.02 (m, 15H).

Example 113(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 521.0 m/z (M+H); H-NMR (DMSO-d₆) δ 8.91-8.78 (m,1H), 7.95-7.70 (m, 2H), 7.63-7.41 (m, 4H), 7.40-7.23 (m, 2H), 6.33-6.23(m, 1H), 5.80-5.64 (m, 1H), 5.23-5.18 (m, 1H), 4.45-4.35 (m, 2H),4.23-4.18 (m, 1H), 3.64-3.58 (m, 1H), 2.10-1.95 (m, 1H), 1.82-1.71 (m,1H), 1.56-1.42 (m, 1H), 1.40-1.05 (m, 10H).

Example 114(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 521.0 m/z (M+H); H-NMR (DMSO-d₆) δ 8.91-8.80 (m,1H), 7.70-7.62 (m, 2H), 7.60-7.43 (m, 4H), 7.37-7.32 (m, 2H), 6.33-6.28(m, 1H), 5.78-5.72 (m, 1H), 5.23-5.18 (m, 1H), 4.45-4.35 (m, 2H),4.23-4.18 (m, 1H), 3.64-3.59 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.71 (m,1H), 1.56-1.42 (m, 1H), 1.40-1.05 (m, 10H).

Example 115(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 420.1 m/z (M+H); H-NMR (DMSO-d₆) δ 8.10-8.05 (m,1H), 7.53-7.50 (m, 2H), 7.36-7.30, (m, 3H), 6.33-6.28 (m, 1H), 5.74-5.69(m, 1H), 5.22-5.15 (m, 1H), 4.23-4.17 (m, 1H), 3.70-3.60 (m, 1H),3.26-3.22 (m, 1H), 2.71 (d, 3H), 2.01-1.97 (m, 1H), 1.83-1.77 (m, 1H),1.56-1.45 (m, 1H), 1.33-1.06 (m, 9H).

Example 116(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 524.1 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.43, 7.42-7.40, 7.37-7.24, 7.21-7.11,6.30-6.23, 5.86-5.75, 5.21-5.15, 4.68, 4.62, 4.24-4.18, 3.73-3.61,3.07-2.97, 2.89, 2.86, 2.28, 2.15, 2.02-1.96, 1.83-1.76, 1.53-1.45,1.41-1.26, 1.24-1.18.

Example 117(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 511.3 m/z (M+H); H-NMR (DMSO-d₆) δ 8.72 (t, 1H),8.35 (d, 1H), 7.57-7.50 (m, 3H), 7.35-7.33 (m, 3H), 7.15 (d, 1H), 6.29(d, 1H), 5.74-5.69 (m, 1H), 5.21-5.15 (m, 1H), 4.35 (d, 1H), 4.22-4.18(d, 1H), 3.64-3.58 (m, 1H), 2.39 (s, 3H), 2.00-1.96 (m, 1H), 1.82-1.76(m, 1H), 1.50-1.44 (m, 1H), 1.32-1.24 (m, 8H).

Example 1187-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 548.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.51-7.26, 7.12-7.03, 7.02-6.98, 4.82, 4.80-4.70,3.63-3.58, 3.50-3.39, 2.93, 2.89-2.81, 2.80, 2.78-2.63, 2.60-2.45,1.96-1.91, 1.76-1.70, 1.42-1.20, 1.19-1.04.

Example 1197-{5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 560.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.42, 7.35-7.20, 7.18-7.09, 6.88-6.81, 4.73,4.61, 4.44, 3.78, 3.63-3.60, 3.50-3.42, 3.35-3.20, 2.95-2.85, 2.82,2.80-2.63, 2.62-2.50, 1.96-1.92, 1.76-1.70, 1.33-1.22, 1.20-1.13.

Example 1207-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 566.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.42, 7.34-7.12, 4.70, 4.68, 3.63-3.61,3.47-3.42, 2.91, 2.89, 2.76-2.72, 2.69-2.65, 1.97-1.92, 1.77-1.72,1.42-1.27, 1.18-1.13.

Example 1217-{5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 560.1 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.42, 7.33-7.25, 7.18-7.04, 4.72, 4.56, 4.43,3.79, 3.77, 3.71-3.60, 3.51-3.40, 3.38-3.33, 2.95-2.83, 2.81, 2.78-2.63,2.60-2.43, 1.96-1.92, 1.76-1.71, 1.42-1.21, 1.19-1.14.

Example 1227-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 566.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.40, 7.37-7.25, 7.18-7.08, 7.06-7.00, 4.86,4.76, 4.72, 3.64-3.57, 3.52-3.40, 3.24-3.21, 2.97, 2.93-2.76, 2.75-2.60,2.58-2.48, 1.96-1.91, 1.76-1.70, 1.42-1.20, 1.18-1.00.

Example 1237-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 562.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.55-6.93, 4.73, 4.69, 4.66, 3.65-3.61, 3.49-3.45,2.90, 2.87, 2.74-2.71, 2.69-2.67, 2.26, 2.23, 2.20, 1.95-1.90,1.74-1.69, 1.45-1.12.

Example 1247-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 578.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.09, 6.84-6.76, 4.75, 4.70, 3.77, 3.68,3.65-3.61, 3.51-3.47, 2.88, 2.74, 2.73-2.68, 2.59-2.56, 2.26, 1.97-1.91,1.77-1.07.

Example 1257-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 544.2 m/z (M+H); H-NMR (DMSO-d₆) δ [Mixture ofrotamers at 25° C.] δ 7.75-7.40, 7.33-7.08, 7.06-6.98, 4.60, 4.48,3.64-3.58, 3.45-3.38, 2.95-2.84, 2.82, 2.77-2.45, 2.18, 2.15, 1.96-1.91,1.76-1.70, 1.43-1.22, 1.18-1.14.

Example 1267-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 544.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.65-7.40, 7.33-7.22, 7.18-7.02, 4.74, 4.58, 4.45,3.64-3.58, 3.45-3.38, 2.95-2.84, 2.82, 2.77-2.45, 2.18, 2.15, 1.96-1.91,1.76-1.70, 1.43-1.22, 1.18-1.14.

Example 1277-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 578.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.58-7.57, 7.49-7.44, 7.33-7.29, 7.14-7.10,7.03-6.95, 4.75, 4.66, 4.62, 3.83, 3.80, 3.64-3.60, 3.49-3.46, 2.89,2.85, 2.74-2.67, 2.59-2.52, 1.94-1.90, 1.74-1.68, 1.42-1.11.

Example 1287-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 544.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.48, 7.47-7.40, 7.33-7.27, 7.19-7.13,7.07-6.97, 4.72, 4.68, 4.64, 3.64-3.62, 3.49-3.45, 2.91, 2.87,2.76-2.72, 2.68-2.60, 2.21, 2.15, 1.96-1.92, 1.77-1.71, 1.57-1.29,1.17-1.11.

Example 1297-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: H-NMR (DMSO-d₆) [Mixture of rotamers at 25° C.] δ 7.59,7.51-7.40, 7.34-7.28, 6.97, 4.73-4.71, 3.62-3.60, 3.49-3.45, 2.93, 2.87,2.76-2.72, 2.71-2.636, 1.94-1.90, 1.74-1.68, 1.43-1.26, 1.17-1.12.

Example 1307-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 560.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.50-7.26, 7.18-6.96, 4.73, 4.68, 4.63, 3.85,3.70, 3.63-3.59, 3.49-3.42, 2.90, 2.87, 2.75-2.70, 2.61-2.57, 1.96-1.91,1.76-1.70, 1.56-1.13.

Example 1317-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 560.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.55-7.39, 7.33-7.29, 7.09-7.01, 4.68, 4.65, 3.80,3.76, 3.63-3.61, 4.47-3.45, 2.90, 2.86, 2.72-2.68, 2.52-2.49, 2.47,2.46, 1.96-1.91, 1.76-1.70, 1.47-1.12.

Example 1327-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 89: MS (APCI⁺) 544.3 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofrotamers at 25° C.] δ 7.63, 7.51-7.47, 7.38-7.32, 7.29-7.14, 7.07-6.99,4.74, 4.69, 4.63, 3.62-3.60, 3.48-3.45, 2.93-2.89, 2.87, 2.83,2.73-2.70, 2.63-2.57, 2.18, 2.03, 1.93-1.89, 1.73-1.68, 1.37-1.12.

Example 1331-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid (3-fluoro-benzyl)-methyl-amide

To a7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt (270 mg, 0.49 mmol) in MeCN (50 ml) was slowly addedTFA (1.0 mL, 1.23 mmol). The reaction mixture was stirred at 25° C. andmonitored by HPLC. After 2 hrs, the reaction was completed. The reactionmixture was diluted with EtOAc (150 ml) and washed with H₂O, saturatedNaHCO₃, and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by silica gel columnchromatography (70% EtOAc/Hex) to afford1-(4-fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid (3-fluoro-benzyl)-methyl-amide (210 mg, 84%): MS (APCI⁺) 512.2 m/z(M+H); H-NMR (CDCl₃) [Mixture of rotamers at 25° C.] δ 7.40-7.21,7.18-6.88, 4.72, 4.611, 4.58-4.48, 4.33-4.24, 2.98-2.93, 2.80-2.68,2.63, 2.63 2.62, 2.61, 2.57, 2.56, 2.55, 2.17-2.14, 1.80-1.63,1.61-1.58, 1.31-1.29.

Example 1341-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid benzyl-methyl-amide

The title compound was prepared in a manner analogous to the method ofExample 133: MS (APCI⁺) 494.2 m/z (M+H); H-NMR (CDCl₃) [Mixture ofrotamers at 25° C.] δ 7.38-7.24, 7.17-7.10, 4.74, 4.61, 4.58-4.51,4.33-4.28, 3.00-2.90, 2.80-2.70, 2.64-2.63, 2.62-2.57, 2.08-2.03,1.75-1.63, 1.61-1.57, 1.32-1.28, 1.25-1.22.

Example 1351-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid 4-methyl-benzylamide

The title compound was prepared in a manner analogous to the method ofExample 133: MS (APCI⁺) 494.1 m/z (M+H); H-NMR (CDCl₃) δ 7.35-7.32 (m,2H), 7.24-7.10 (m, 6H), 4.56-4.51 (m, 3H), 4.32-4.30 (m, 1H), 2.95-2.89(m, 1H), 2.79-2.72 (m, 1H), 2.68-2.67 (m, 1H), 2.59-2.54 (m, 1H), 2.30(s, 3H), 1.83-1.56 (m, 3H), 1.38 (d, 6H).

Example 136(3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid sodium salt

The title compound was prepared in a manner analogous to the method ofExample 1: MS (APCI⁺) 552.2 m/z (M+H); H-NMR (DMSO-d₆) [Mixture ofdiastereomers] δ 7.68-7.43, 7.41-7.19, 5.93-5.83, 5.23-5.15, 4.78-4.69,4.55-4.42, 3.70-3.58, 3.56-3.42, 2.99-2.83, 2.80-2.63, 2.62-2.51,1.97-1.88, 1.86-1.63, 1.62-1.53, 1.49-1.12.

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. Accordingly, the invention is limited only by the followingclaims.

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, C₁-C₇alkyl, C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl of R₁ is optionally substituted; R₂ isR_(2b)R_(2a)NCO(CH₂)_(n)— or R_(2b)-J-C(O)NR_(2a)(CH₂)_(n)—; J is adirect bond, O, or N; R_(2a) and R_(2b) are each independently hydrogen,C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl of R_(2a) and R_(2b) is optionally substituted; or R_(2a)and R_(2b) taken together with the nitrogen to which they are attachedform a 4-11 member ring optionally containing at least one additionalheteroatom selected from O, N and S, said ring being optionallysubstituted with at least one of aryl, aralkyl, heteroaryl,heteroaralkyl, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₈ cycloalkyl,halogen, R⁷O—, R⁷OOC(CH₂)_(n)—, R⁷R⁸NCO(CH₂)_(n)—, R⁷O₂S(CH₂)_(n)—,R⁸R⁷NSO₂— or NC—; R⁷ and R⁸ are each independently hydrogen, C₁-C₁₂alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R⁷ and R⁸ isoptionally substituted; n is 0, 1 or 2; R₃ is hydrogen, C₁₋₆ alkyl,C₃₋₈cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; wherealkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₃ isoptionally substituted; and --- is a bond or is absent.
 2. A compoundaccording to claim 1 having the following (3R,5R) stereospecific formula(Ia):


3. A compound according to claim 1 having the structural formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R_(2a) andR_(2b) are each independently hydrogen, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl,aryl, aralkyl, heteroaryl or heteroaralkyl; where alkyl, cycloalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl of R_(2a) and R_(2b) isoptionally substituted; or R_(2a) and R_(2b) taken together with thenitrogen to which they are attached form a 4-11 member ring optionallycontaining at least one additional heteroatom selected from O, N and S,said ring being optionally substituted with at least one of aryl,aralkyl, heteroaryl, heteroaralkyl, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl,halogen, R⁷O—, R⁷OOC(CH₂)_(n)—, R⁷R⁸NCO(CH₂)_(n)—, R⁷O₂S(CH₂)_(n)—,R⁸R⁷NSO₂— or NC—; R⁷ and R⁸ are each independently hydrogen, C₁-C₁₂alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R⁷ and R⁸ isoptionally substituted; n is 0, 1, or 2; and --- is a bond or is absent.4. A compound according to claim 3, wherein R_(2a) is:

Where R₄ and R₅ are each independently hydrogen or lower alkyl; q is 0,1 or 2; each R₆ is independently hydrogen, halogen, alkyl, haloalkyl,alkoxy, or cyano; and p is 0, 1, 2, 3, 4, or
 5. 5. A compound accordingto claim 4 having the following (3R,5R) stereospecific formula (IIa):


6. A compound according to claim 1 having the structure of formula(III):

or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 6 having the following (3R,5R) stereospecific formula (IIIa):


8. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, C₁-C₇alkyl, C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl of R₁ is optionally substituted; R₂ isR_(2b)R_(2a)N(CH₂)_(n)— or R_(2b)-J-C(O)NR_(2a)(CH₂)_(n)—; J is a directbond, O, or N; R_(2a) and R_(2b) are each independently hydrogen, C₁-C₁₀alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ofR_(2a) and R_(2b) is optionally substituted; or R_(2a) and R_(2b) takentogether with the nitrogen to which they are attached form a 4-11 memberring optionally containing at least one additional heteroatom selectedfrom O, N and S, said ring being optionally substituted with at leastone of aryl, aralkyl, heteroaryl, heteroaralkyl, C₁-C₁₀ alkyl, C₃-C₈cycloalkyl, halogen, R⁷O—, R⁷OOC(CH₂)_(n)—, R⁷R⁸NCO(CH₂)_(n)—,R⁷O₂S(CH₂)_(n)—, R⁸R⁷NSO₂— or NC—; R⁷ and R⁸ are each independentlyhydrogen, C₁-C₁₂ alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl ofR⁷ and R⁸ is optionally substituted; n is 0, 1 or 2; R₃ is hydrogen,C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ofR₃ is optionally substituted; and --- is a bond or is absent.
 9. Acompound according to claim 8 having the following stereospecificformula (IVa):


10. A compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, C₁-C₇alkyl, C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl of R₁ is optionally substituted; R₂ isR_(2b)R_(2a)NCO(CH₂)_(n)— or R_(2b)-J-C(O)NR_(2a)(CH₂)_(n)—; J is adirect bond, O, or N; R_(2a) and R_(2b) are each independently hydrogen,C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl of R_(2a) and R_(2b) is optionally substituted; or R_(2a)and R_(2b) taken together with the nitrogen to which they are attachedform a 4-11 member ring optionally containing at least one additionalheteroatom selected from O, N and S, said ring being optionallysubstituted with at least one of aryl, aralkyl, heteroaryl,heteroaralkyl, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, halogen, R⁷O—,R⁷OOC(CH₂)_(n)—, R⁷R⁸NCO(CH₂)_(n)—, R⁷O₂S(CH₂)_(n)—, R⁸R⁷NSO₂— or NC—;R⁷ and R⁸ are each independently hydrogen, C₁-C₁₂ alkyl, aryl oraralkyl; where alkyl, aryl or aralkyl of R⁷ and R⁸ is optionallysubstituted; n is 0, 1 or 2; R₃ is hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl of R₃ is optionallysubstituted; and --- is a bond or is absent.
 11. A compound according toclaim 1 selected from the group consisting of:(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoicacid;7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoicacid;7-{5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoicacid;7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoicacid;7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoicacid;3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoicacid;3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoicacid;3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-heptanoicacid;7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoicacid;7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoicacid;7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoicacid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoicacid;7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;7-[5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoicacid;7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid;7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid; and(3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoicacid; or a pharmaceutically acceptable salt thereof.
 12. A compound ofclaim 11, wherein said pharmaceutically acceptable salt is a sodiumsalt.
 13. A compound according to claim 8 selected from the groupconsisting of:1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid (3-fluoro-benzyl)-methyl-amide;1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid benzyl-methyl-amide; and1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylicacid 4-methyl-benzylamide; or a pharmaceutically acceptable saltthereof.
 14. A pharmaceutical composition comprising a compound of claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, solvent or vehicle.
 15. A method oftreating a subject suffering from hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benignprostatic hypertrophy (BPH), diabetes and osteoporosis comprisingadministering a therapeutically effective amount of at least onecompound of claim 1, or a pharmaceutically acceptable salt thereof. 16.A combination comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a second pharmaceutically active agent. 17.The combination of claim 16, wherein said second pharmaceutically activeagent is a CETP inhibitor, a PPAR-activator, an MTP/Apo B secretioninhibitor, a cholesterol absorption inhibitor, HDL-cholesterol raisingagent, triglyceride lowering agent, a cholesterol synthesis inhibitor, acholesterol modulating agent, a fibrate, niacin, an ion-exchange resin,an antioxidant, an ACAT inhibitor, bile acid sequestrant, ananti-hypertensive agent, or an acetylcholine esterase inhibitor.
 18. Thecombination of claim 16 further comprising a pharmaceutically acceptablecarrier, diluent, solvent or vehicle.
 19. (canceled)
 20. (canceled)